Deadly Diseases and Epidemics - Plague, 2nd Edition (121p)

Plague
Second Edition
Antibiotic-resistant Malaria, Second
Bacteria Edition
Anthrax, Second Edition Meningitis
Avian Flu Mononucleosis,
Botulism Second Edition
Campylobacteriosis Pelvic Inflammatory
Cervical Cancer Disease
Chicken Pox Plague, Second
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Polio
Dengue Fever and Other
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Syndrome Smallpox
Helicobacter pylori Staphylococcus
Hepatitis aureus Infections
Herpes Streptococcus (Group A)
HIV/AIDS Streptococcus (Group B)
Infectious Diseases Syphilis,
of the Mouth Second Edition
Infectious Fungi Tetanus
Influenza, Toxic Shock Syndrome
Second Edition
Trypanosomiasis
Legionnaires’ Disease
Tuberculosis
Leprosy
Lung Cancer Tularemia
Lyme Disease Typhoid Fever
Mad Cow Disease West Nile Virus,
(Bovine Spongiform Second Edition
Encephalopathy) Yellow Fever
plague
Second Edition
Donald Emmeluth, Ed.D.

CONSULTING EDITOR
Hilary Babcock, M.D., M.P.H.,
Infectious Diseases Division,
Washington University School of Medicine,
Medical Director of Occupational Health (Infectious Diseases),
Barnes-Jewish Hospital and St. Louis Children’s Hospital
FOREWORD BY
David Heymann
World Health Organization
Plague, Second Edition
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Emmeluth, Donald.
Plague / Donald Emmeluth ; Consulting Editor, Hilary Babcock ; Foreword by
David Heymann. — 2nd ed.
p. cm. — (Deadly diseases and epidemics)
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Table of Contents

Foreword
David L. Heymann, World Health Organization 6
1. Historical Overview 8
2. Causes of the Plague 19
3. Cats, Rats, Prairie Dogs, and Squirrels 32
4. Diagnosis 41
5. Treatment 51
6. Prevention 60
7. The Problems of Antibiotic Resistance 69
8. Concerns for the Future 79
9. Hopes for the Future 86
Notes 99
Glossary 102
Further Resources 108
Index 112
About the Author 120
About the Consulting Editor 120

Foreword
Communicable diseases kill and cause long-term disability. The
microbial agents that cause them are dynamic, changeable, and resilient:
they are responsible for more than 14 million deaths each year, mainly
in developing countries.
Approximately 46 percent of all deaths in the developing world are
due to communicable diseases, and almost 90 percent of these deaths
are from AIDS, tuberculosis, malaria, and acute diarrheal and respira-
tory infections of children. In addition to causing great human suffer-
ing, these high-mortality communicable diseases have become major
obstacles to economic development. They are a challenge to control
either because of the lack of effective vaccines, or because the drugs
that are used to treat them are becoming less effective because of anti-
microbial drug resistance.
Millions of people, especially those who are poor and living in
developing countries, are also at risk from disabling communicable
diseases such as polio, leprosy, lymphatic filariasis, and onchocerciasis.
In addition to human suffering and permanent disability, these com-
municable diseases create an economic burden—both on the work force
that handicapped persons are unable to join, and on their families and
society, upon which they must often depend for economic support.
Finally, the entire world is at risk of the unexpected communi-
cable diseases, those that are called emerging or reemerging infections.
Infection is often unpredictable because risk factors for transmission are
not understood, or because it often results from organisms that cross the
species barrier from animals to humans. The cause is often viral, such
as Ebola and Marburg hemorrhagic fevers and severe acute respiratory
syndrome (SARS). In addition to causing human suffering and death,
these infections place health workers at great risk and are costly to econ-
omies. Infections such as Bovine Spongiform Encephalopathy (BSE)
and the associated new human variant of Creutzfeldt-Jakob Disease
(vCJD) in Europe, and avian influenza A (H5N1) in Asia, are reminders
of the seriousness of emerging and re-emerging infections. In addition,
many of these infections have the potential to cause pandemics, which
are a constant threat our economies and public health security.
Science has given us vaccines and anti-infective drugs that have
helped keep infectious diseases under control. Nothing demonstrates

Foreword
the effectiveness of vaccines better than the successful eradication of

smallpox, the decrease in polio as the eradication program continues,
and the decrease in measles when routine immunization programs are
supplemented by mass vaccination campaigns.
Likewise, the effectiveness of anti-infective drugs is clearly dem-
onstrated through prolonged life or better health in those infected
with viral diseases such as AIDS, parasitic infections such as malaria,
and bacterial infections such as tuberculosis and pneumococcal
pneumonia.
But current research and development is not filling the pipeline
for new anti-infective drugs as rapidly as resistance is developing,
nor is vaccine development providing vaccines for some of the most
common and lethal communicable diseases. At the same time pro-
viding people with access to existing anti-infective drugs, vaccines,
and goods such as condoms or bed nets—necessary for the control
of communicable diseases in many developing countries—remains a
great challenge.
Education, experimentation, and the discoveries that grow from
them, are the tools needed to combat high mortality infectious diseases,
diseases that cause disability, or emerging and re-emerging infectious
diseases. At the same time, partnerships between developing and indus-
trialized countries can overcome many of the challenges of access to
goods and technologies. This book may inspire its readers to set out on
the path of drug and vaccine development, or on the path to discovering
better public health technologies by applying our present understanding
of the human genome and those of various infectious agents. Readers
may likewise be inspired to help ensure wider access to those protec-
tive goods and technologies. Such inspiration, with pragmatic action,
will keep us on the winning side of the struggle against communicable
diseases.
David L. Heymann
Assistant Director General,
Health Security and Environment
Representative of the Director General for Polio Eradication
Geneva, Switzerland
1
Historical Overview
The word plague is defined as a dangerous disease that spreads rapidly
and often causes death. It is synonymous with a cause of suffering or
harm. If we mention the bubonic plague or, better yet, the Black Death,
the name brings to mind a series of well-known historical events that
resulted in the death and suffering of millions of people. But this is not
just an event of the past. Each year, in the United States, between 10 and
30 individuals are infected with the organism that causes bubonic plague,
Yersinia pestis. New Mexico alone averages seven to eight cases a year.
There were no human cases in New Mexico in 2004, five human cases in
2005, eight in 2006, and five in 2007; six of those infected died during that
period from 2005 through 2007.1 Yersinia pestis is endemic to the Ameri-
can Southwest; it is always present at low levels. Bubonic plague occurs in
more than 20 countries worldwide, with an average of more than 2,000
total cases per year.
The following is a fictionalized version of an event that occurred in
New York City in November 2002. The names of the hospital, doctors, and
hospital administrators are accurate. It should be remembered that both
the city and country were still extremely concerned about bioterrorism
in the wake of September 11, 2001, and the anthrax attacks in the fall of
the same year. The death of several people from anthrax had everyone on
edge, and none more so than the medical community.
The Trip
Husband and wife John Tull and Lucinda Marker had saved for months
in order to make the trip. They had been looking forward to seeing New
York City in the fall. Although Santa Fe, New Mexico, was a medium-

Historical Overview
sized city, it lacked the character and excitement of New

York City. And there was also Ground Zero. The World Trade
Center destruction area was a magnet for many, and John
and Lucinda were among those who felt drawn to make the
pilgrimage.
Both John and Lucinda came down with fevers and flu-like
symptoms at the same time, shortly before their trip. They took
some over-the-counter medication and drank plenty of fluids.
They were determined that this little discomfort was not going
to stop their trip. And so, congested and feverish, they boarded
the plane and winged their way to the Big Apple.
New York City in the fall can be an imposing place. Winds
blowing between the buildings and down the streets create
a windchill factor that shocks visitors from the Southwest.
Yet, John and Lucinda did not feel terribly cold because their
fevers had not abated. Unfortunately, John was feeling weak
and had difficulty walking for any length of time. Lucinda
felt a swelling in her groin region, and the area in her armpits
were feeling tender and also seemed swollen. Both agreed that
they needed to contact a doctor. Before they left Santa Fe, they
had had their family doctor provide them with the name of a
physician they could contact in the New York area. When they
contacted Dr. Ronald Primas and described their symptoms,
he made an immediate appointment to have them examined.
He was concerned that they might have smallpox, West Nile
virus, anthrax, possibly the plague or — he hoped — just the
flu. Once Dr. Primas saw the couple and examined Lucinda,
however, it was clear that she probably had bubonic plague.
John’s symptoms were also consistent with that diagnosis.
That initial diagnosis was strengthened when the couple men-
tioned that a rat on their property had tested positive for the
plague the previous July. The bacteria that cause the plague
are constantly present in low concentrations in fleas that live
on rats, squirrels, and domesticated dogs and cats throughout
the Southwest.
10 plague
Number of Plague Cases by County, 1970–2002
Figure 1.1 Although many people think of plague as something from

the Middle Ages, it is actually endemic, especially in the Southwest of
the United States. Today, however, plague is rarely deadly as it was in
medieval times. (Centers for Disease Control and Prevention [CDC])
Dr. Primas referred the couple to Beth Israel Medical

Center. The patients were placed in isolation, and the New
York City Department of Health was notified. None of the
doctors in the hospital had ever seen a case of plague. Though
the form of plague that the couple had was not contagious,
it could become so if not treated within a few days. Health
Department personnel gave the couple a new diagnostic test
Historical Overview 11
that involved checking their blood for the presence of certain

types of protective proteins called antibodies. This test was
part of a series of new tests developed since the September
11 attacks. The tests came back positive for bubonic plague.
It was clear that the couple had contracted the disease back
home in New Mexico and that this was not an instance of bio
terrorism. After a few days of antibiotic treatment, Lucinda
was released from the hospital and John was making a slow,
modest recovery.
The Present-day Plague

It may seem hard to believe that a disease that presumably
caused the death of millions during the fourteenth, fifteenth,
and sixteenth centuries is still active in the United States in the
twenty-first century. In actuality, between 10 and 30 people in
the United States are infected yearly. Plague appears in about
15 states, with most cases occurring in the West (Figure 1.1).
According to the Centers for Disease Control and Preven-
tion (CDC), between 1,000 and 3,000 people worldwide are
infected annually. Dr. Thomas Frieden, health commissioner
of New York City, indicates that half of all cases in the United
States originate in New Mexico in Santa Fe County, the county
where Lucinda and John live. Fleas that attach themselves to
wild animals carry the disease organism. Fleas are the vec-
tors, or carriers of the disease. The large rodent population in
Santa Fe County is the suggested cause of the large number of
infections in the area.
The Black Death

Historical records suggest that a plague began in Egypt in a.d.
541, affecting a significant portion of the known world. It is
estimated that 50 to 60 percent of the population died from
that pandemic (a worldwide disease outbreak).
Researchers at the University of Sheffield in England dis-
covered archeological evidence in March 2004 suggesting that
Egypt and North Africa might be the site of origin of the plague
12 plague
bacteria. Dr. Eva Panagiotakopulu and her colleagues found

that the flea that is the major carrier of the plague organism
was native to the Nile Valley. This flea is a parasite of the Nile
rat. Around 3500 b.c., people began to build cities near the Nile,
thus disturbing the Nile rats and providing a new place for the
rats to visit—the newly constructed homes. Egyptian writings
mention outbreaks of a disease with symptoms similar to the
plague. The Ebers Papyrus, a medical text from 1500 b.c., identi-
fies a disease that causes a swollen area, known as a bubo, filled
with pus. It is not difficult to envision that as sea trade devel-
oped between Egypt and places such as India, rats on those
seafaring ships picked up plague-loaded fleas and carried them
to Europe and beyond.2
The second great plague pandemic began in 1346. It
became known as the Black Death, or the Great Pestilence,
because of the distinctive symptoms that the disease produced.
Symptoms included a swelling of regional lymph nodes in the
groin and under the arms. These swellings are called buboes.
Ulcerations were common on the skin, but the most distinctive
feature was the dark color beneath the skin where blood vessels
had ruptured, turning the skin black in those areas. Hence, the
disease was given the name the “Black Death.”
Within five years of the 1346 outbreak, more than 13
million people had died in China, and, in Europe, the dis-
ease may have killed 3 out of every 4 people it infected. The
plague continued over the next 300 years, killing between
20 and 30 million people in Europe. (It seemed to disappear
around 1670.) Recent work in England suggests that victims
of the Black Death in England between 1347 and 1351 were
more often the weak rather than the strong. Evidence sug-
gests that the victims were already in bad health, often from
poor diets.3
Historical records indicate that a third pandemic began
in China in the mid-1850s. Its distribution seems to have
paralleled the expansion of the Chinese Empire. As Chinese
troops moved into regions of Burma, India, and Hong Kong,
the plague organism moved with them. It continued to spread

aboard steamships that went to European and American
ports. This pandemic ended around 1910.
Whenever and however the plague organism became
established in the United States, it spread into the western
and southwestern portions of the country. Most human cases
occur in northern New Mexico, northern Arizona, southern
Colorado, California, southern Oregon, and far western
Nevada. Between 1989 and 2003, 38,310 cases of plague were
reported to the World Health Organization. These figures
included 2,845 deaths from 25 countries.4 In 2002, the total
number of reported plague cases in 13 countries was 1,925, of
which 177 were fatal. In 2003, nine countries reported 2,118
cases including 182 deaths. These figures indicate a decrease
when compared with the annual average figures (2,895 cases,
206 deaths) for the previous 10 years (1992-2001), when
28,956 cases with 2,064 deaths were reported from 22 coun-
tries. Cases of plague have been reported nearly every year
during that same period from eight countries: Democratic
Republic of the Congo, Madagascar, United Republic of Tan-
zania, Peru, United States, China, Mongolia, and Vietnam.
Since 1994, there have been three new outbreaks of human
plague that occurred in three countries after 30 to 50 years
without reports of any new cases. The first was in India in
1994, where more than 5,000 cases were reported, resulting in
disruption to travel and international trade, with devastating
economic effects. A smaller outbreak of bubonic plague involv-
ing six cases occurred in Indonesia in 1997. The third was an
outbreak in Algeria in 2003, where 10 confirmed cases and one
probable case were reported.5
Bubonic plague continues to be endemic (constantly
present, though with few cases) in many areas of the world.
The Cause
The causative agent of bubonic plague was identified
by Alexandre Yersin in 1894. He recognized that it was
14 plague
caused by a bacterium that ultimately was named after him,

Yersinia pestis.
Yersin, who worked for the Pasteur Institute in France,
developed a treatment that was marginally effective in combat-
ing the disease and was the first to suggest that rats and fleas
were responsible for transmission of the organism during the
epidemic of 1894 in Hong Kong.
Figure 1.2 Alexandre Yersin, who identified the causative agent of

the bubonic plague in 1894. (© SPL/Photo Researchers, Inc.)
Figure 1.3 Alexandre Yersin in front of his hut in Hong Kong, where
he isolated the plague germ. (CDC)
In an attempt to produce a vaccine to protect people

against bubonic plague, Yersin inoculated horses with increas-
ing doses of the plague organism that had been killed by heat.
Yersin’s team of assistants then had to remove blood from the
horses. They separated the fluid portion (the plasma) from
the blood cells and inactivated the various proteins that cause
blood to clot. The plasma with the clotting factors removed is
known as the serum and is the portion of the blood that con-
tains the antibodies against the plague organisms. These anti-
bodies are designed to neutralize the protein toxins released
by the bacteria. The vaccine varied in quality, and horses fre-
quently died from the process. Yersin had hoped to produce
more than 7,000 doses of the vaccine but was persuaded to go
to India with only his available vaccine doses.
16 plague
In 1897, Alexander Yersin left the Pasteur Institute and

entered Bombay Harbor with 700 doses of his antiplague
serum. After two months of treating patients, nearly half had
died. A new batch of serum from France increased the sur-
vival rate to 80 percent. However, the Bombay government
began to restrict Yersin’s access to patients. He was allowed to
inject only those patients who were already too far advanced
in their illness to be helped. When the Pasteur Institute
recalled him, Yersin left Bombay without regret.
The symptoms of bubonic plague usually begin to
emerge within one to seven days after a person is bitten
by an infected flea. Symptoms usually include fever and
swelling in the regional lymph nodes in the groin, armpit,
or neck regions. There are many additional symptoms that
may occur. The disease organism may spread to the lungs or
bloodstream and the central nervous system. The fatality rate
when this happens is nearly 100 percent.
Black Death Was Not

Necessarily Bubonic Plague
Not everyone believes that the bubonic plague organism
caused the plague known as the Black Death. Two scientists
from the Liverpool University School of Biological Sciences in
England have published a book that places Europe’s plague in
a new historical, geographical, and demographic perspective.
Using parish burial registers, Susan Scott and Christopher
Duncan have shown that, although many of the symptoms
match the bubonic plague, other factors, such as incubation
times and transmission agents, do not. In their book, The
Biology of Plagues, they show that the incubation period is
too long and that the type of rats most likely to carry the
infected fleas did not migrate into England until 50 years
after the plague had ended in 1670. Quarantine measures are
ineffective against bubonic plague, but they were successful
against the Black Death. Scott and Duncan concluded after
Simond Says
Dr. Paul-Louis Simond picked up plague research where Alexan-

der Yersin left off. The prevailing sentiment of the day was that
transmission of the plague was human to human. Yersin had
hypothesized that rats were the main vectors. In spite of the
prevailing wisdom, Simond began to uncover the evidence that
would show that the fleas carried by rats were the main vectors
of the disease. He developed a deceptively simple experiment
that showed that the fleas killed the rat and then sought a new
warm host—a human being. Simond published his work with
the simple recommendation that the key to controlling plague
was to keep rat populations in check. His work was met with
silence or scorn. He remains a forgotten hero.6
an exhaustive review of described symptoms and primitive

autopsy results that the Black Death was probably caused by a
virus distantly related to Ebola.
James Wood, professor of anthropology and demography at
Penn State University, shares the opinion that bubonic plague was
not the cause of the Black Death. Wood and several colleagues
and graduate students have analyzed bishops’ records of the
replacement of priests during the time period of 1349 to 1350.
From these records, Wood concluded that the disease spread
much too rapidly among humans without being established in a
wild rodent population first. Additionally, there were no records
of widespread die-offs of rats in the streets or countryside. The
disease spread rapidly along roadways and rivers, and was not
slowed by the geographical barriers that normally would have
stopped or restricted the movement of rodents. Wood and his
colleagues have not ruled out the possibility that the causative
agent might be an ancestor of the modern plague organism that
mutated into the present form.
18 plague
The French and English

Continue to Disagree
In another twist, researchers from Oxford University and
Barts and London Hospital attempted to confirm reports of
a French team that claimed to have isolated bits of Yersinia
pestis DNA from the teeth of disinterred plague victims. The
English team presented their results to the Society of General
Microbiology at a conference in Manchester, England, in Sep-
tember 2003. They were unable to replicate the results of the
French team. They found no Yersinia pestis DNA in any of the
teeth of the victims they examined. They suggested that one
future possibility would be to find a plague victim buried in
the permafrost with enough preserved DNA to make a final
determination.
Whether or not the Black Death and the bubonic plague
are one and the same, the bubonic plague has caused enor-
mous human devastation and has resulted in many changes
in health and medical practices.
2
Causes of the Plague
Donner Memorial State Park near Truckee, California, closed on Tuesday,
August 27, 2002. It would not reopen again until the spring of 2003.
This would not seem to be a terribly unusual event except that the park
normally stayed open much longer. The immediate cause of this closing
was confirmation of the plague in two squirrels, and the appearance of
plague symptoms in a cat from a nearby park campground. Chipmunks
and squirrels in the area had previously tested positive for the bubonic
plague organism. “The Truckee area has a history of infected animals,”
said Vicki Kramer, chief of vector-borne diseases for the California
health department.
It has been quiet in the Donner Pass region recently, but other sections
of the West and Southwest have picked up the slack. In 2006, a campground
at Natural Bridges National Monument in Utah was closed for three weeks
after the plague organism was detected in chipmunks and mice in the area.
Colorado had several cases of plague involving cats and squirrels. The cats
were thought to have become infected by eating infected rodents. In 2007, a
monkey at the Denver zoo died of bubonic plague. It was thought the monkey
contracted the disease by eating an infected squirrel. Five other squirrels and
a rabbit were found dead of the plague on the grounds of the zoo. Arizona
saw its first case of human plague since 2000 in September of 2007. Nearly
two months later Eric York, a wildlife biologist working at Grand Canyon
National Monument, was found dead at his home. Test results showed he had
died of the plague. Evidence suggests he probably contracted the disease as
the result of performing an autopsy on a dead mountain lion.1
In 2008, a Boy Scout from Connecticut was diagnosed with the plague.
He and other scouts had been doing service projects in Yellowstone,
19
20 plague
Bridger-Teton National Forest, and other sites in Wyoming.

Before that, the last case of human plague in Wyoming had
occurred in 2004. In Santa Fe County, New Mexico, the plague
capital of the United States, a cat contracted the plague in its
pneumonic form in January 2008. This respiratory form is con-
sidered the most deadly. The cat coughed constantly, and it was
feared it might have sprayed family members with the deadly
organism. The family members were treated with antibiotics,
and all survived. Unfortunately, the cat died.2
Origin of the Plague Organism

There are three human pathogenic, or disease-causing, species
of the genus Yersinia: Yersinia pestis, which is the causative
agent of the plague; Yersinia pseudotuberculosis; and Yersinia
enterocolitica. The latter two species cause intestinal prob-
lems. Y. enterocolitica (for simplicity, genus names are often
abbreviated), the most common of the three species and a
very common form of foodborne sickness, causes inflamma-
tion of the intestines, a condition known as gastroenteritis.
Y. pseudotuberculosis, the least common of the three, causes
fever and abdominal pain that may mimic the symptoms of
appendicitis.
Many scientists suggest that the bubonic plague organ-
ism has been around for millions of years. Dr. Victor Suntsov,
of the Severtsov Institute of Ecology and Evolution in the
Russian Academy of Sciences, suggests that the plague organ-
ism originated between 15,000 and 20,000 years ago in Mon-
golian marmots (small rodents similar to squirrels). Suntsov
contends that the plague microorganism evolved as a mutant
form of Yersinia pseudotuberculosis in a population of mar-
mots in Mongolia, Manchuria, and Transbailkal.
What Are Bacteria?

Living things on this planet currently are placed into five
large categories called kingdoms. These are the Kingdoms
Causes of the Plague 21
Plantae (plants), Animalia (animals), Fungi, Protista, and

Prokaryotae (bacteria).
The cells of all living organisms are organized in one of
two ways. Cells from the plant, animal, fungi, and protista
kingdoms all contain compartments constructed from inter-
nal cellular membranes. These compartments, which help
separate chemicals and other materials from the interior of
the cell, are called organelles, or miniature organs. Organelles
include the nucleus, the lysosome, and the mitochondria.
This type of cellular organization, with clearly defined and
identifiable organelles, is described as the eukaryotic type
of cellular organization. The term eukaryotic means “true
nucleus” and comes from the Greek eu, meaning “true,” and
karyon, meaning “nucleus.” Therefore, cells of plants, ani-
mals, fungi, and protozoa are known as eukaryotic cells, or
eukaryotes, because of their internal cellular organization.
The bacteria, or Prokaryotae, kingdom includes cells
with a different type of internal organization. Bacterial cells
lack membrane-defined organelles, are normally smaller
than eukaryotic cells, and have few clearly defined inter-
nal structures. Because bacteria lack organelles such as the
nucleus, they are described as being prokaryotic cells. The
word prokaryotic comes from the Greek pro, for “before,”
and karyon, meaning “nucleus.” Because bacterial cells do
not have a nucleus, the genetic information (a single circular
DNA molecule) resides in the cell with no membrane struc-
ture surrounding it. This type of cellular organization has
served bacteria well for over 3.5 billion years.
Important Bacterial Structures

Bacteria were originally classified as very small plants
because, like plants, they have a cell wall protecting their cell
membrane and the interior of the cell. However, bacterial
cell walls are made of molecules that are different from the
molecules in plant cell walls. Bacterial cell walls are made of
22 plague
Archaea — A Third Form of Life

Another group of microorganisms also has a prokaryotic type
of cellular organization. They are called the archaebacteria,
or simply the archaea, and they resemble bacteria in size
and prokaryotic organization. However, the archaea are quite
different genetically from both eukaryotic and prokaryotic
types of cells. Archaea contain genetic information similar to
the eukaryotes and also genetic information similar to bacte-
ria. In addition, more than 40 percent of their genetic infor-
mation is totally unique, resembling neither eukaryotes nor
bacteria. The archaea live in extreme environments, earn-
ing them the name “extremophiles.” Extreme environments
include the absence of oxygen or places with very high heat,
such as inside volcanoes.
a molecule called peptidoglycan that contains amino acids,

which are building blocks made of proteins (peptido) and
carbohydrates, which include simple sugars such as glucose
(glycan). Because this unique molecule is not found among
eukaryotes (including humans), the human immune system
tries to remove or destroy it.
Bacteria have differing amounts of peptidoglycan in their
cell walls. When treated with different dyes, these differences
in the amount of peptidoglycan and other factors cause bac-
terial cells to retain or lose the color of specific dyes (Figure
2.1). One very famous and important staining reaction used
to differentiate between bacteria is the Gram’s stain process.
In this process, bacteria are treated with a series of different-
colored dyes. If the bacteria retain the first dye color (crystal
violet) throughout the entire staining procedure, they are
called gram-positive bacteria. Other bacteria lose the first dye
in the process and take on the color of the last dye (called the
counterstain). These bacteria look pink or light red and are
called gram-negative bacteria.
Figure 2.1 One way to test for the presence of the

plague bacterium, Yersinia pestis, is with a procedure
known as a Wright’s stain, which takes a blood sample
from a suspected plague patient and uses dye to detect
bacteria in the blood. The darkened stains that indicated
that the person has Yersinia pestis can be clearly seen on
this sample of a Wright’s stain. (Centers for Disease Con-
trol and Prevention [CDC])
It is also important to know that bacteria can move on their

own if they possess a structure called a flagellum (a whip-like tail).
A flagellum (plural is flagella) helps the bacterium move toward
areas where there is food and security and away from harmful
areas. Flagella are made from a unique protein called flagellin.
Because humans do not produce this protein, when the human
immune system recognizes flagellin, it works to destroy it.
The unique molecular structure of bacterial cell walls and
flagella is important to our understanding of the vaccines and
drugs used against bubonic plague. For example, the unique
structure of the peptidoglycan molecule makes it a target for
antibiotics, such as penicillin, that have been very successful
in killing the bacteria that cause many illnesses, including
bubonic plague.
24 plague
Characteristics of Yersinia pestis

Bacteria come in three basic shapes. A single bacterium
shaped like a rod or a pencil is known as a bacillus (plural is
bacilli). A bacterium shaped like a circle or a sphere is known
as a coccus (plural is cocci). A bacterium that is shaped like
a spiral or the letter “c,” or is wound tightly like a spring, is
known as a spirillum (plural is spirilli).
The bacterium responsible for bubonic plague is called
Yersinia pestis. It is named after Alexandre Yersin, who discov-
ered it in 1894 while investigating the plague in Hong Kong.
Yersin had originally named the organism Pasteurella pestis
in honor of his mentor, Louis Pasteur. It is a small, stubby,
gram-negative, oval- to rod-shaped bacterium. It is a faculta-
tive anaerobe, an organism that uses oxygen when it is present
but can also live and reproduce in an anaerobic (oxygen-free)
environment. Yersinia pestis tends to grow slowly in culture
and produces small colonies.
When treated with certain dyes and staining techniques,
Yersinia pestis creates an unusual staining pattern called bipo-
lar staining, which mimics a closed safety pin. Though this
bipolar staining is not unique to Yersinia pestis, it is one of its
many distinctive diagnostic characteristics.
Factors Involved in Yersinia’s Virulence

Yersinia pestis can multiply within a wide range of tempera-
tures (–2°C to 45°C; 28.4°F to 113°F) and pH values (5.0 to
9.6), but optimal growth occurs at 28°C (82.4°F) and at a pH
of about 7.4. The bacterium is nonencapsulated, or lacking a
capsule or envelope, when it grows at its optimal growth tem-
perature of 28°C. When grown at temperatures higher than
28°C, the organisms produce an envelope glycoprotein, called
fraction 1 (F1). The genes for production of this glycoprotein
are encoded in a plasmid. The F1 glycoprotein serves as an
antiphagocytic capsule and allows the bacterium to obtain
iron from its host. It also plays a role in the survival of the
bacteria within the gut of a flea.
The bubonic plague organism, like other members of its

family, the Enterobacteriaceae, is gram-negative. This is the
same family that includes the common intestinal bacterium
Escherichia coli and the Salmonella organisms, including the
one that causes typhoid fever. The cell walls of gram-negative
bacteria contain less peptidoglycan than those of gram-posi-
tive bacteria. The outermost layer of the cell wall of gram-
negative bacteria also contains lipopolysaccharide (LPS) and
proteins. Because LPS is toxic to mammals, it is called an
endotoxin. When the bacterium dies, the LPS becomes free in
the serum. Blood is divided into the formed elements (red and
white blood cells and platelets) and the fluid portion, known
as the plasma. When clotting factors, such as various proteins,
are removed or neutralized, the light yellow fluid that is left is
the serum. The serum contains the immune proteins known
as antibodies; when free LPS interacts with these antibod-
ies, a number of problems arise in humans, including fever,
changing blood cell counts, and leaking blood vessels, which
can lead to shock. This outer layer, also called the outer mem-
brane, has an inside and an outside. The outside of the mem-
brane contains the LPS. Part of this polysaccharide chain is a
series of repeating sugar units known as O antigen. The name
is derived from the fact that the polysaccharide is exposed to
the outer environment. Host defenses can hone in on these
sugars; however, bacteria can change the makeup of the O
antigen to confuse the human host’s immune system.
The outermost region of the cell wall is made of an inner
phospholipid layer and an outer lipopolysaccharide layer.
Just outside the cell membrane is a layer of peptidoglycan.
Yersinia’s cell wall is unlike that of other members of the
Enterobacteriaceae family due to lack of O antigen side-
chains. These O antigen side-chains are missing because a
group of the bacteria’s genes is disrupted.
The V (virulence) and W antigens are protein-lipoprotein
complexes in the cell wall. These antigens make it difficult for
white blood cells to engulf the bacteria. One important reason
26 plague
that Yersinia pestis is so virulent is its ability to survive and

multiply within cells of the immune system. Antibodies produced
against the V antigen provide protection against the plague
organisms. Although it is not clear exactly how the V antigen
works, it is obvious that it does multiple things. Any plague
vaccine would include V antigen as an important component.
A protein called invasin on the outer membrane aids the
bacterium in attachment to human cells. Another protein
called plasminogen activator is an enzyme that aids in the
spread of the bacteria. This enzyme prevents fibrin molecules
from creating a clot formation that would trap the bacteria at
the site of the fleabite.
It has been suggested that a single gene mutation may be
responsible for the level of virulence in Yersinia pestis. Writing
in the May 2008 issue of the journal Microbiology, Professor
Robert Brubaker of the University of Chicago explained that
the organism needs calcium to be able to grow at body tem-
perature. When calcium is not available to the organism, it
produces an excessive amount of the amino acid, aspartic acid.
Most bacteria produce the enzyme aspartase, which breaks
down aspartic acid; Yersinia pestis lacks the ability to produce
this enzyme. The subsequent buildup of aspartic acid in the
patient causes an imbalance in the amino acid pool, which
seems to increase virulence and lethality. Brubaker suggests that
developing a therapy that would reduce the aspartic acid load
would reduce the death rates.3
Needling the Host Cell

How do bacteria deliver toxins into a cell? The answer for
a number of human pathogens, including Salmonella, Shi-
gella, Chlamydia, Escherichia coli 0157:H7, and Yersinia, is a
molecular machine called the type III secretion system. The
structure looks like a thumbtack or pushpin that you might
put into a bulletin board (Figure 2.2).
This molecular machine is made of 29 proteins that, when
assembled, “function as a syringe-like organelle spanning the cell
Figure 2.2 Plague has a unique way of infecting itself into a host
cell. Once the bacterium’s virulence genes have been activated,
Yersinia pestis clamps on to a cell and acts almost like a syringe
to force itself past the cell membrane. This process is sometimes
referred to as “Yersinia’s deadly kiss.”
membrane and anchored in the inner and outer membranes”

of the cell wall, as explained by Dr. Susan Straley from the Uni-
versity of Kentucky. Straley further explains how the needle-like
molecular machine works: “When the needle—the part that
sticks out—comes in contact with a host cell, it punctures the
cell and samples the cytoplasm. In response to the low calcium
environment inside the cell, the bug’s [bacteria’s] secretion
mechanism is activated, and it sends toxins right into the host
cytoplasm.”4
The toxins Straley mentioned are Yops (Yersinia outer
p roteins). Eleven of these proteins have been identified. They
are structurally and functionally diverse, and include protein
kinases, protein phosphatases, proteases, and GAP proteins.
28 plague
These proteins collectively overcome the host’s natural defenses

and make it difficult for the phagocytic white blood cells to
become aware of the bacteria’s presence. Once inside the host
cell, they disrupt the cytoskeleton of the host cell, allowing the
bacteria to multiply and spread within the host cell. “These Yops
mimic key cell biological reactions and modify them in a way
that is advantageous to the bacteria,” Straley says. “One of the
bug’s early high-priority activities is to prevent being engulfed
and destroyed by macrophages and PMNs (polymorphonucle-
ated neutrophils); three of these Yops participate in that.”
To summarize, the Yersinia pestis organism reproduces
most rapidly at 27 to 28°C (80.6–82.4°F) but does not produce
the protein toxins that are responsible for human symptoms at
that temperature. When the microbe encounters a human cell
with a temperature range of 36 to 38°C (96.8–100.4°F), its rate
of reproduction slows, but it begins to produce the apparatus
needed to inject these proteins into its new human host. Also,
at the higher temperatures, the microbes produce a capsule that
makes it difficult for white blood cells to engulf them.
The Life of the Flea

Fleas survive best in a climate that is warm and moist—15
to 20°C (59–68°F) and 90 to 95 percent humidity. Changes
in the seasons lead to temperature and humidity fluctuations
that affect the life span and the level of activity of fleas. In
most flea species, Yersinia pestis reproduces most rapidly at
temperatures in the range of 26 to 28°C (78.8–82.4°F).
A flea acquires the disease by biting an infected host such
as a rat or squirrel. After the microbe enters the flea’s body, it
reproduces rapidly and creates a plug of bacteria in the region
between the esophagus and the stomach. This plug prevents
effective digestion by the flea. When the flea bites a human, the
plug of bacteria is regurgitated into the new host’s wound. The
plague bacteria now begin to reproduce in the host’s blood,
causing the typical symptoms of plague and, possibly, the
death of the host.
Figure 2.3 Some pathogens, such as the plague-causing bacterium

Yersinia pestis, escape phagocytosis and thus destruction by a host
cell by commanding the cell to commit suicide. By releasing a pro-
tein into the host cell (blue cell at top), Yersinia activates host-cell
proteins called caspases. Once activated, caspases trigger events in
the cell that break down the DNA in the nucleus, switch off and dis-
integrate the mitochondria (the energy-producing cell organells), and
precipitate a rearrangement of the cell’s surrounding plasma mem-
brane. This chain of events finally leads to decomposition of the cell
into smaller pieces and release of the bacterium into the tissue. The
green cells are macrophages, which have ingested the cell pieces
that have undergone apoptosis.
diFFereNT maNiFesTaTioNs oF The plague

After the flea has found its new mammalian host, it takes
a bite and injects some of the plague bacilli into the host’s
bloodstream. Some of the host’s immune system cells—large,
modified white blood cells called macrophages—are invaded
by the plague organisms before the immune system recognizes
30 plague
the danger. Ironically, the bacteria find a safe place to live

inside those cells whose job is supposed to be to destroy for-
eign organisms.
As the immune system becomes aware of the invasion,
phagocytic white blood cells called polymorphonucleated
neutrophils (PMNs) begin to gear up for action. The PMNs
destroy many of the bacteria but are overwhelmed by the
sheer numbers of the microbes. Additionally, the microbes
begin to produce capsules and other proteins that prevent
destruction by the PMNs. At this point, the microbes may
enter the lymphatic system. This fluid-filled system runs par-
allel to the circulatory system and has a series of collection
regions known as lymph nodes. The lymph nodes have large
accumulations of PMNs, macrophages, and other chemical
agents. The bacteria that enter the lymphatic system are fil-
tered through the lymph nodes, and a battle is joined between
the bacteria and the immune system cells and chemicals. This
battle causes an inflammatory reaction that signals additional
cells to join the fight. It also results in a swollen lymph node
known as a bubo. This feature is diagnostic of the bubonic
form of the plague. It usually takes from 2 to 7 days for a
swollen lymph node to develop after the fleabite. The lymph
carries the bacteria back into the bloodstream, where they
enter the liver and the spleen. Many bacteria are undoubtedly
killed by immune system cells in these organs, but their sheer
number tends to overwhelm the body’s defenses.
Some bacteria can wind up in the lungs, producing a highly
contagious and extremely dangerous form of plague. Known as
pneumonic plague, the bacteria can be spread from person to
person by coughing. According to Dr. Susan Straley, inhaling as
few as 100 of the bacteria can cause pneumonic plague. Given
the fact that scientists estimate each square centimeter of our
skin holds an average of 100,000 bacteria, these 100 bugs pack
an extraordinary punch.
Because the inhaled bacteria have already adapted to the

body of the first person, they arrive fully armed with their
toxin-delivery mechanism. Straley says this gives the bacteria a
head start in the race against the body’s defenses. As in bubonic
plague, the bacteria first encounter macrophages — in this case,
alveolar macrophages, the lungs’ defense cells. “Some of the
bacteria go into macrophages, you get an influx of PMNs and
then inflammation. Part of inflammation is fluid influx, so your
lungs fill up, and you can’t breathe,” says Straley. “The bacteria
also spread to the lymph nodes and the blood, so the basic pro-
cess is the same as in bubonic plague, but we really know very
little about the specifics. As little as one day after inhalation you
start showing severe symptoms of pneumonia, and the next
day you could be dead.” Straley adds that this is a very narrow
window for correct diagnosis and treatment.
Septicemic plague may occur as a complication of either
bubonic or pneumonic plague. It is not spread from person to
person but is characterized by the presence of bacteria in the
bloodstream. Of the three forms, pneumonic plague is the most
deadly and the fastest killer.
3
Cats, Rats, Prairie Dogs,
and Squirrels
Jim was going to spend a few days with a friend in Alberquerque,
New Mexico. Jim had met Zachary in India that previous summer at the
All India Institute as part of a program to learn about the health-care sys-
tem of a large urban city. When their time in India ended, the new friends
exchanged e-mail addresses and promised to visit each other.1
Zachary lived south of Santa Fe, about 25 miles (40 km) away from
Albuquerque. He was a student at the University of New Mexico in
Albuquerque.
Mid-April in Albuquerque and Santa Fe meant high temperatures
ranging between 60 and 70°F (15.6–21.1°C) and low temperatures
between 35 and 45°F (1.7–7.2°C). The previous year had been wetter
than normal.
First Stop—The Hospital?

When Jim stepped off the plane, Zachary was waiting to greet him. They
got into Zachary’s car and headed out of the airport. “The university is
along the way, so we’ll stop there and you’ll also get a chance to meet my
dad,” proclaimed Zachary.
“That’s great,” said Jim. “Does your father work at the university?”
asked Jim.
“No,” said Zachary, “he’s in the university hospital.”
“What’s wrong with him?” asked Jim, hoping he had not made the trip
at the wrong time.
“He’s got bubonic plague,” stated Zachary, showing little emotion in
his voice.
32
Cats, Rats, Prairie Dogs, and Squirrels 33
“bubonic plague!” shouted Jim.

“Apparently you didn’t do your homework before you
came to this area of New Mexico,” said Zachary. “If you had, you
would have known that New Mexico has an average of seven to
eight cases of plague each year. The Santa Fe area has become
somewhat famous in the last few years for plague cases. Have
you heard of John Tull and Lucinda Marker?” asked Zachary.
“Can’t say that I have,” replied Jim.
Zachary continued: “They are a married couple who became
infected by the plague organism from the fleas of a dead rat on
their property near Santa Fe. They went to New York for a vaca-
tion and wound up in the hospital there. Caused quite a stir at
the hospital, since none of the doctors had ever seen a plague
case before, and now they had two patients at once. John was in
bad shape and spent a long time recovering.”
Zachary explained that John became so ill that the doctors
had to amputate both of his legs below the knee.
Zachary’s car pulled up next to a building with a sign that
said Health Sciences Center. “Here’s where I spend most of my
time on campus. We can walk over to the university hospital
after I take you on a quick tour of the facilities.” Jim was happy
to get out and stretch his legs again, but he was flabbergasted
at this turn of events. He had never seen a person who had
bubonic plague. If he remembered his microbiology correctly,
the plague was also called the Black Death. What would
Zachary’s father look like? Would his extremities be all black
and gangrenous? Zachary didn’t seem that concerned. As a
matter of fact, Zachary appeared to be no more concerned than
if his father had contracted a cold. As they walked, Zachary
explained how his father had contracted the disease.
Weekend at Camp
Three weeks before, Zachary’s father, Al, had visited a friend in
an area near Bluewater Lake in northwestern New Mexico, not
far from Albuquerque. They were going to do some repairs on
the friend’s hunting cabin. Rodents had gnawed through some
34 plague
of the wooden planks, and the cabin was open to the environ-
ment. Among the unwanted guests in the cabin were a number
of dead rock squirrels. Since it had been a tough winter, the
dead squirrels did not seem unusual. Al and his friend used
gloves and carefully removed the squirrels and burned their
bodies in a large bonfire. They noticed that the squirrels had
acquired large numbers of fleas. Some had crawled onto Al’s
arms and bitten him. His friend was also bitten by the fleas.
They used a pesticide spray to kill the fleas. Unfortunately for
them, the damage had already been done.
After a weekend of repair work on the cabin, Al headed
for home. He was beginning to feel like he was coming down
with the flu. His throat was sore, his body ached, and he felt
alternately feverish and then chilled. He would have dismissed
all of these symptoms except for the fact that he was start-
ing to feel weak and had itchy fleabites on his arms and legs.
The regional lymph nodes under his arms and in his groin
region were swollen and tender to the touch. Al called home
on his cell phone and spoke to Zachary. He told Zachary he
was going directly to the hospital and would call after he had
checked in. Al had lived in New Mexico long enough to know
that symptoms like his could easily mean bubonic plague. His
friend joined him in the hospital the following day.
Al had indeed contracted bubonic plague. Going directly
to the hospital had saved his family from having to take anti-
biotics. If he had come home and interacted with the family,
all of the members would have to take antibiotics as a precau-
tion against contracting the disease. Without prompt treat-
ment, the first symptoms would be flulike—fever and chills,
headache, tiredness, and constipation or diarrhea. The most
obvious sign would be an enlarged lymph node, called a bubo,
in the area adjacent to the flea bite. Incubation takes one to
six days, when sepsis sets in. Abdominal involvement may
lead to muscle tenderness and potential vomiting, seizures,
or bleeding. Depending on the area of the bite, there may be
gangrene as well.
As Zachary and Jim got to the hospital room, Al greeted

a somewhat hesitant Jim with a big smile and the reassurance
that he was not contagious. Al was responding nicely to the
antibiotic therapy and was looking quite well. He would soon
be coming home. If Jim had not known of the illness, he would
never have guessed that Al had bubonic plague. He now under-
stood why Zachary did not appear to be concerned about his
father’s health.
What Types of Animals Carry the Plague

Organism?
As is true with many diseases, humans are not the primary
host of the disease organism Yersinia pestis. Human infection
is accidental or incidental, and depends on the chance contact
Figure 3.1 Tree squirrels are a known carrier of Yersinia pestis.

(© Anatoli Dubkov/shutterstock)
36 plague
between humans and the infected fleas of infected rodents. In

other words, Zachary’s dad was in the wrong place at the wrong
time. Animal hosts, such as the rock squirrels, usually begin to die
off in increasing numbers before humans are likely to be infected,
because the fleas of the dying rodents will be seeking new hosts.
Zachary’s dad did not see or recognize the increase in the number
of dead squirrels. He only saw the dead squirrels in the cabin.
Different Levels of Infection

Some animal groups are fairly resistant to the impact of the
plague organisms. Mice of the genus Microtus or the genus
Peromyscus are considered enzootic reservoirs of the infec-
tion. This means that the frequency of the plague organism is
maintained at a low level in the population of host organisms
(the mice), resulting in low mortality rates. This difference in
Figure 3.2 The Norway rat, shown here, is another carrier of the
plague bacterium Yersinia pestis. (Centers for Disease Control and
Prevention [CDC])
Figure 3.3 Plague is spread through the bite of infected fleas, which
acquire the bacterium from rats and other rodents that are carriers
of Yersinia pestis. This is an oriental rat flea, or Xenopsylla cheopis.
The dark mass in its lower body, which scientists call a proventricular
plague mass, is evidence that the flea is infected with plague. (CDC)
resistance to the plague organism varies from one geographi-

cal region to another.
In contrast, there are a number of animal species that
are highly susceptible to the Yersinia pestis organism. These
species seem to be clustered in the western part of the United
States and represent the greatest threat to the human popula-
tion. The hosts are mostly rodents that die in large numbers,
causing the fleas to change hosts. This group of highly suscep-
tible animals is called an epizootic reservoir. Included in this
group are urban and domestic rats, ground squirrels, rock
squirrels, prairie dogs, gerbils, voles, chipmunks, marmots,
guinea pigs, and kangaroo rats.
Although rodents get most of the blame, larger mammals
can also introduce infected fleas to humans or to other animal
species. Coyotes, badgers, rabbits and hares, deer, antelope, goats,
38 PLAGuE
sylvaTiC aNd urBaN plague
When plague organisms are found mainly in the fleas of rodents,

such as squirrels, in areas away from where humans live, the dis-
ease is called sylvatic plague. Infection is accidental and inci-
dental, and is usually not the cause of epidemics. When plague
organisms are found in the fleas of rats in and around densely
populated cities, the disease is called urban plague. This kind
of plague has traditionally been the cause of epidemics.
Sylvatic Cycle Urban Cycle
Figure 3.4 Although humans most often get plague from the bite of
an infected flea, this diagram shows some of the other possible ways
to catch the disease.
Table 3.1 Plague Testing by Species, Colorado 2007
Species Positive Negative Total Tested

Cat 8 70 78
Prairie Dog 4 22 26
Flea 13 17 30
Rabbit 3 44 47
Rock Squirrel 0 3 3
13-Liner Squirrel 0 6 6
Tree Squirrel 50 251 301
Monkey 1 0 1
Bear 0 1 1
Mouse 0 5 5
Rat 0 1 1
Dog 0 5 5
Beaver 0 1 1
Fox 0 6 6
Lynx 2 1 3
Raccoon 0 2 2
Coyote 17 95 112
Total 98 530 628
Source: Colorado Department of Public Health and Environment, “Plague Testing by Species,
Colorado 2007, as of 08/31/07,” http://www.cdphe.state.co.us/dc/zoonosis/plague/Plague_
cases_07.pdf.
camels, cats, and sometimes dogs can all transmit the fleas to
human beings. As humans and their animal pets continue to
expand their living quarters into the habitats of wild mammals
and rodents, increased contact is inevitable. With this increased
contact comes the likelihood of transmitting disease organisms
between species.
An international group of scientific researchers working
in Kazakhstan have linked climatic changes to epidemics and
large-scale outbreaks of bubonic plague among humans. Evi-
dence shows that as the spring weather became warmer and
the summers wetter the organisms causing the plague became
40 plague
more ubiquitous. It seems that the fleas that carry the plague
bacterium become more active when temperatures rise above
50°F (10°C). Warm, frost-free spring weather allowed the fleas
to begin breeding earlier, thus allowing the population to
increase in size. If this was followed by a moist, humid summer
the flea population continued to grow. The study showed that
a two-degree rise in spring temperatures led to an almost 60
percent increase in the incidence of the disease. The research-
ers used tree-ring analysis to show that the weather conditions
at the time of the major plague pandemics were both warmer
and wetter.2
4
Diagnosis
About 20 minutes after leaving the hospital, Zachary pulled into the driveway
of his home. Zachary’s brother Garrett greeted them. “Dad called and said
you were on the way and that Jim had arrived on time,” said Garrett. “I made
some coffee and Mom said you could have some of the cake in the refrig-
erator. She’ll be home in about an hour.” Zachary thanked his brother as he
poured a cup of coffee for himself and one for Jim. After bringing in Jim’s
luggage and getting him settled in the guest room, the two young men sat out
on the back porch and enjoyed the warmth of the coffee and the crispness
of the fresh air.
“You wanted to know how they figured out that my dad really had the
plague. You asked the right person, so sit back and I’ll give you an overview of
what happens,” said Zachary. Trying to diagnose a disease strictly on the basis
of its symptoms is not very useful, Zachary explained, since many diseases
have similar symptoms. Everything from the flu to various types of food
poisoning may have symptoms including headache, fever, chills, body aches,
and overall weakness. Diagnosis of bubonic plague requires that health-care
workers carry out laboratory tests on the patient’s blood, sputum (material
coughed up from the lungs), or the fluid taken from an enlarged or swollen
lymph node (a bubo). Suspected plague organisms can be stained using a
Gram’s stain or Wayson’s stain. Usually, a chest X-ray is taken to determine
whether the plague organism is causing pneumonia. Diagnosis of the differ-
ent forms of the plague involves modifications of some of the techniques.
Forms of the Plague

The same bacterium can cause three different forms of plague. The bubonic
form is best known because of the swollen and tender lymph nodes called
41
42 plague
Figure 4.1 A plague patient with a swollen lymph node, known as a

bubo. (Centers for Disease Control and Prevention [CDC])
Figure 4.2 An X-ray of a plague infection involving both lungs.

Rapidly developing pneumonia is one of the first signs of plague. (CDC)
Diagnosis 43
buboes. If the organisms invade the bloodstream, they may

cause destruction of blood vessels under the skin, leading to the
darkened or blackened areas that gave the Black Death its name.
Usually, the patient’s high fever, over 104°F (40˚C), leads to
delirium and, in more than half of all untreated cases, death.
The bacterium may invade the lungs and cause a pneu-
monic form of the disease. This form is extremely contagious
and is the most dangerous form, since it is spread from person
to person through aerosol droplets. Every time the patient
coughs or sneezes, he or she may contaminate people in the
area. Victims of this form of plague usually develop a severe
cough and eventually bloody sputum. Pneumonic plague leads
to coma and death in nearly 100 percent of untreated cases.
The third form of plague occurs when large numbers
of the bacteria enter the bloodstream. This is known as the
Figure 4.3 One possible effect of the plague is the development of

gangrene, in which the affected body part turns turn black because of
insufficient blood flow. This person is suffering from gangrene of the
fingers. Gangrene is extremely dangerous because it can lead to the
amputation of the rotted body part. (CDC)
44 plague
septicemic form. It normally causes gangrene in various

body areas, and death usually occurs within a day or two.
Untreated, all infected people die from this form of plague.
Diagnosis of Bubonic Plague

The incubation period for the bubonic form of the plague
ranges from 2 to 10 days. Patients are often tired, have a fever
as high as 105°F (40.6°C), and exhibit tender lymph nodes,
particularly in the groin region or areas near the fleabite. The
liver and spleen may also be tender. About one-fourth of all
bubonic plague patients may have skin lesions. A presumptive
diagnosis is usually made microscopically when gram-
Summary of Laboratory Diagnosis

for Suspected Plague Cases
Staining of Specimens
• Appropriate clinical specimens include: Blood,

bubo aspirates, sputum, cerebrospinal fluid (CSF) (if
there are signs/symptoms of meningitis), and skin
scrapings (if a lesion is present).
• Gram’s stain: Polymorphonuclear leukocytes and bipo-

lar staining, “safety pin” ovoid, gram-negative cocco-
bacilli identified in bubo aspirate, sputum, blood, or CSF
are highly suggestive of plague.
• Wayson stain: Yersinia pestis appears as light blue

bacilli with dark blue polar bodies on a contrasting pink
ground.
• Immunofluorescent staining of capsule (F1): A

positive finding is diagnostic. Must use fresh speci-
mens to avoid false negatives. This test is available
only at reference laboratories.
Diagnosis 45
negative coccobacillary cells show a “safety pin” or bipolar

staining pattern. This staining pattern is the result of granules
that are localized in the ends of the cell. The sample may be
taken from a lymph node, sputum, or cerebrospinal fluid. If
it is available, immunofluorescent staining can also provide
useful information.
A definitive diagnosis is made when the organisms are
cultured on various microbiological media such as blood
agar, MacConkey agar, or infusion broth. Y. pestis does not
have many enzymatic functions, such as adenine deaminase,
aspartase, ornithine decarboxylase, glucose-6-phosphate
dehydrogenase, and urease. It primarily utilizes glucose and
Bacterial cultures
• Blood, bubo aspirates, sputum, CSF, and skin scrapings
can be cultured.
• Materials should be inoculated into blood and MacCon-
key agar plates and infusion broth. It generally takes two
days to identify visible colonies. Rapid biochemical iden-
tification systems may not be reliable for identification
due to slower growth rate of Y. pestis.
Serologic Testing
• Several serologic tests are available, including a passive
hemagglutination test. A fourfold or greater rise
is diagnostic, a single titer (concentration) of >1:16
in someone without prior immunization against plague is
suggestive. Serology is not useful for rapid diagnosis.
Source: Medical Treatment and Response to Suspected Plague: Informa-

tion for Health Care Providers During Biologic Emergencies, New York City
Department of Health, Bureau of Communicable Disease. Available online
at http://www.nyc.gov/html/doh/html/cd/plaguemd.shtml.
46 plague
mannitol, and cannot ferment most carbohydrates. It grows

on sheep blood agar with little or no hemolysis, and forms
gray-white colonies with a shiny appearance after about 48
hours. The colony borders are irregular, and are often termed
“fried-egg.” Positive cultures that display the above charac-
teristics are considered evidence of Y. pestis infection, and are
reported and forwarded, if necessary, to state authorities for
further identification and confirmation.
Laboratory Diagnosis and Safety

Microscopic examination of stained samples from body flu-
ids and the use of immunofluorescent stains provide the first
evidence of the possibility of Yersinia pestis infection. The
diagnosis is confirmed through serology, in which character-
istics of a disease are shown through the study of proteins
in blood serums, but because serologic tests can take several
days to perform, it is not useful if a rapid diagnosis is needed.
Serologic tests check levels of antibodies to specific Yersinia
antigens. These levels are low early in disease. If antibodies
against the bacterial capsule (F1 antigen) are found to have
increased at least fourfold a few weeks after infection in a
patient with no history of plague vaccination, then this con-
firms the diagnosis.
Handling Laboratory Specimens

Laboratory work on those suspected of having Y. pestis
infection should be done in biosafety level 2 facilities, using
standard and special practices, equipment, and facility speci-
fications. For example, staff must wear surgical gloves, pro-
tective gowns, and shoe covers. Staff must make every effort
to avoid splashing or creating an aerosol, and must wear
protective eyewear and masks if work cannot be done in a
biosafety level 2 cabinet.
Yersinia pestis is classified as a select agent, one with the
potential to pose a severe threat to public health and safety, and,
therefore, its handling is regulated under strict federal guide-
lines. These provide requirements for laboratories that handle
Diagnosis 47
Figure 4.4 The Laboratory Response Network (LRN) was founded in

1999 by the Centers for Disease Control and Prevention to ensure an
effective national bioterrorism response system. The LRN was reorga-
nized in 2002 into sentinel, reference, and national laboratories. Sen-
tinel (formerly Level A) laboratories include most clinical labs with at
least biosafety level 2 (BSL-2) containment. These labs receive sam-
ples, rule out ordinary pathogens, and refer for additional testing. Ref-
erence (formerly Levels B and C) laboratories include mostly state or
local public health labs with BSL-3 containment facilities with access
to nonpublic testing protocols and chemicals. These labs perform
limited confirmation testing and refer for additional testing. They also
perform diagnostic identification tests, and refer for additional testing.
National (formerly Level D) laboratories have BSL-4 containment facili-
ties. They perform the definitive identification testing for the highest
level of agent characterization.
48 plague
select agents such as Y. pestis, including registration, secu-

rity risk assessments, safety plans, security plans, emergency
response plans, training, transfers, record keeping, inspections,
and notifications. The requirements went into effect on Febru-
ary 7, 2003. They supersede earlier government requirements
for the handling and transfer of particular agents.
In 1999, a network of laboratories was developed by the
Centers for Disease Control and Prevention—partnered with
the Federal Bureau of Investigation and the Association of
Public Health Laboratories—to coordinate all clinical diagnos-
tic testing for suspected bioterrorism events. The Laboratory
Response Network (LRN) links public health laboratories to
private hospital, clinical, and referral labs that normally send
suspected select agents to the public health labs for confirma-
tion. The Laboratory Response Network depends upon vol-
untary cooperation among laboratories. It requires that labs
assess their capabilities relative to the biosafety requirements
needed to perform the types of analysis normally done by labs
at biosafety levels 1 and 2 (BSL-1 and BSL-2).1
The LRN was originally divided into four categories: Levels
A through D, based on their capabilities. In 2002 the LRN was
reorganized (see Figure 4.1). There are now only three catego-
ries of labs (Figure 4.4): sentinel (formerly level A), reference
(formerly levels B and C), and national (formerly level D).
Sentinel laboratories can perform the standard initial tests
designed to rule out (but not definitively identify) Y. pestis.
Sentinel labs include Clinical Laboratory Improvement Act
(CLIA)–certified clinical laboratories with BSL-2 safety equip-
ment and practices. The protocols for sentinel laboratories
include Gram’s stains, spot tests, and other simple tests such as
motility. The intent is to rule out agents of bioterrorism. The
majority of these labs are hospital based, clinical institutions
and commercial diagnostic laboratories. These labs play a key
role in the early detection of biological agents.
Reference laboratories have the ability and capacity for
agent isolation and confirmatory testing and include most state
public health laboratories. These laboratories are expected to
Diagnosis 49
Summary of recommended
biosafety levels (BSL)
for infectious agents
s Safety Equip- Facilities
ment (Primary (Secondary
BSL Agents Practices Barriers) Barriers)
1 Not known to cause Standard Not required Open bench top
disease in healthy microbiological sink required
adults practices
2 Associated with BSL-1 practice plus: Primary barriers: BSL-1 plus: autoclave
human disease; limited access, Class I or II BSCs* available
hazard: auto- biohazard warning or other physical
inoculation, ingestion, signs, “Sharps” containment devices
mucous membrane precautions, biosafety used for all
exposure manual defining manipulations of
any needed waste agents that cause
decontamination or splashes or aerosols
medical surveillance of infectious materials;
policies PPEs*: laboratory
coats, gloves, face
protection as needed
3 Indigenous or exotic BSL-2 practice plus: Primary barriers: BSL-2 plus: physical
agents with potential controlled access, Class I or II BSCs separation from
for aerosol transmission; decontamination of or other physical access corridors;
disease may have lab clothing before containment devices self-closing, double
serious or lethal laundering, baseline used for all door access; exhausted
consequences serum manipulations exhausted air not
of agents; PPEs: recirculated; negative
protective lab clothing, airflow into laboratory
gloves, respiratory
protection is needed
4 Dangerous/exotic agents BSL-3 practice plus: Primary barriers: BSL-3 plus:

that pose high risk of clothing change all procedures separate building,
life-threatening disease, before entering, conducted in Class III or isolated zone,
aerosol-transmitted lab shower on exit, BSCs or Class I dedicated supply/
infections, or related all material or II BSCs in exhaust, vacuum,
agents with unknown decontaminated combination with and decon systems,
risk of transmission on exit from facility full-body, air-supplied, other requirements
positive pressure outlined in the text
personnel suit
* BSCs = Biosafety cabinets

* PPEs = Personal protection equipment
View the entire CDC/NIH Biosafety Guidelines online at
http://www.research.umich.edu/policies/um/committees/BRRC/BSLChartCDCNIH.html.
50 plague
perform biochemical identification of Brucella, Francisella, Yer-

sinia and Bacillus species to rule in agents of bioterrorism. They
require a minimum of biosafety level 2 and usually 3. Some
of the reference laboratories have advanced capacity for rapid
identification. They require BSL-4 safety equipment and prac-
tices. There are more than 100 state and local public health,
military, veterinary, agriculture, food and water testing labora-
tories included as reference labs. In addition, there are facilities
in Australia, Canada, and the United Kingdom that serve as
reference laboratories outside of the United States. National
laboratories have the highest level of containment (BSL-4) and
expertise in the diagnosis of rare and dangerous biologic agents
and include specialized federal laboratories. Specific informa-
tion about LRN reference and national laboratory protocols for
Y. pestis are not available to the public.2
The National Medical Society provides a very general
online diagnosis of plague based on the patient’s symptoms.
The Centers for Disease Control and Prevention (CDC) pro-
vides a very extensive online manual with a self-assessment
at the end. This is all part of Emergency Preparedness and
Response by the CDC.
5
Treatment
After dinner with Zachary’s family, Jim and Zachary sat down with another
cup of coffee and talked more about the plague.
Zachary said, “It’s really amazing when you consider that an aver-
age of only 10 Yersinia pestis microorganisms need to invade the body
in order to cause bubonic plague. But it’s equally amazing to me that
our bodies use secretions of other bacteria to kill off the first bacteria.
I know that this is a natural series of events that has been occurring for
millions of years. This competition has helped to maintain a balance
between microbes and larger organisms like humans. It’s hard to believe
that until less than a century ago, we had few ways to aid us in the fight
against bacterial diseases. You tend to take antibiotics for granted until
they are needed to cure someone close to you.”
Early Treatments for the Plague

Since their discovery and development in the 1940s, antibiotics have
taken the lead in fighting the effects of bacterial diseases. Prior to the
use of antibiotics, however, people employed a number of unique and
unusual treatments. Some, such as the use of garlic and silver com-
pounds to ward off infection by bacteria, were based on folk medicine
passed down through generations. Others, such as trying to purify the
air with rosemary and thyme, were based on uncritical human observa-
tions that sometimes led to false conclusions.
Before the discovery and study of microorganisms such as bacteria,
European medical thought was dominated by what an Italian historian
named Carlo Cipolla has called the “miasmatic paradigm.” (Miasma
refers to a thick, vaporous atmosphere.) Contagion was thought to
51
52 plague
arise from exposure to unhealthy, “corrupted” air, although

the exact nature of this dangerous influence was
unspecified.
In Seville, Spain, in the 1600s, city officials made residents
clean the streets, burn the clothing and bedding of the sick,
and isolate people who were clearly ill. The officials recom-
mended that people add rosemary and thyme to the air for
the purpose of purification. Variants of these techniques con-
tinue to be used today in some disease settings; for example,
the burning corresponds to sterilization of materials, and
isolation of people with disease is obviously a method of
quarantine.
In today’s world, we know that disease transmission and
prevention is related to sanitary conditions. A clean envi-
ronment reduces the likelihood of disease organisms being
spread from animals to people and between people. That is
why some of the early treatments for the plague, such as bath-
ing in human urine, wearing human excrement, and placing
dead animals in homes (called “stinks”), seem so strange to
us. The use of leeches (a worm-like animal that sucks blood)
was a common mechanism for treating many illnesses. Drink-
ing molten gold (gold heated until it melted) and powdered
emeralds was also recommended but was usually fatal. Some
suggestions, such as eating figs before 6:00 a.m., chopping up
a snake every day, falling asleep on the left side of the bed, or
not sleeping during the day, make no obvious medical sense
and seem to be home-remedy suggestions.
People from all lifestyles sought ways to protect them-
selves from disease. Grave robbers used garlic to protect
against bubonic plague by washing themselves, their clothes,
and stolen items with garlic vinegar. French priests of the
Middle Ages used garlic as well as prayer to protect them-
selves against bubonic plague. Some people thought that cof-
fee had powers great enough to cure the plague. During the
plague of 1664–1665, Gideon Harvey, a well known human
physiologist, published a book entitled Advice Against the
Treatment 53
Figure 5.1 During the Middle Ages (between 500 and

1500), the plague was a terrible threat to humans. It
killed vast numbers of people and devastated the popu-
lation of Europe. Those who could afford to do so often
fled cities during warmer weather, which was considered
“plague season.” This illustration depicts the plague of
London in 1665, which killed tens of thousands.
(© Science Source/Photo Researchers, Inc.)
54 plague
Plague, in which he advised drinking coffee in large amounts.

A 1721 publication by Richard Bradley entitled The Virtue
and Use of Coffee with Regard to the Plague and Other Infec-
tious Distempers; Containing Most Remarkable Observations
also promoted the notion that coffee protected from the
plague. Neither Harvey nor Bradley proved to be correct, but
coffee continued to grow in popularity nonetheless.
Current Treatment
When left untreated, plague can result in rapid death.
Approximately 14 to 17 percent of all plague cases in the
United States each year are fatal. However, if treatment is
received early enough, 5 out of 6 patients survive. “My father
increased his chance of survival by going directly to the hos-
pital,” said Zachary. He informed the hospital admissions
personnel that he thought he had bubonic plague because
of his symptoms and his contact with fleas. Because plague
was suspected, Zachary’s father was immediately isolated,
and local and state departments were notified. Antibiotic
treatment reduces the risk of death to less than 5 percent.
Streptomycin is the preferred treatment and should be given
immediately upon admission to the hospital. Other possible
useful antibiotics include gentamicin, chloramphenicol, tet-
racycline, and trimethoprim-sulfamethoxazole. Doxycycline
is also used for the treatment of plague and is approved by
the Food and Drug Administration (FDA) for this indication.
Rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin
have been shown to be ineffective and should not be used
to treat plague. The Working Group on Civilian Biodefense
also developed consensus-based recommendations for treat-
ment of pneumonic plague during a bioterrorist attack. The
Working Group made the recommendations outlined in
Table 5.1.
The patient’s doctor will determine the specific treat-
ment for plague based on a number of factors, including
Treatment 55
Figure 5.2 A pharmacist creates streptomycin, an antibi-

otic first produced in 1943. Streptomycin is the preferred
treatment for plague. (Hulton-Deutsch Collection/Corbis)
the patient’s age, overall health, and medical history. The

patient’s ability to tolerate specific medications, procedures,
or therapies will also be considered. In each case, the patient
will be hospitalized and medically isolated and given imme-
diate antibiotic treatment. The isolation continues for 48
hours after antibiotic therapy is begun or until cultures are
negative. Gloves are worn at all times when in contact with
56 plague
the infected individual and hospital personnel must avoid

contact with all bodily fluids (urine, sputum, saliva, blood,
and semen).
Treatment of Pneumonic Plague

Treatment for the pneumonic form of plague is different from
other forms because it can be spread from person to person
by droplet transmission (i.e., coughing and sneezing). When
caring for patients with suspected or confirmed plague, hos-
pital personnel must be especially cautious. Patients with
pneumonic plague should be placed on strict respiratory iso-
lation until appropriate antibiotics have been administered
for 48 hours, and the patient shows clinical improvement.
Droplet precautions require that the patient be placed in a
private room and that anyone entering the patient’s room
wear a surgical mask, particularly when standing within three
feet (one meter) of the patient. Because transmission can
occur from plague skin lesions (such as draining buboes or
abscesses) to contacts, if such skin lesions are present, wound
and skin precautions should be followed.
If a person becomes exposed to airborne or aerosolized
Yersinia pestis or comes into close physical contact with a
patient who has a confirmed case of pneumonic plague, he or
she must receive antibiotic therapy referred to as post-exposure
prophylaxis, to prevent disease. Individuals to whom this pre-
caution applies would include people in the same household
and health care workers. All antibiotic therapy should continue
for seven days from the date of the last exposure to the organism
or infected patient.
Treating Environmental Surfaces

Since September 11, 2001, governmental officials have been
concerned about the possible use of bacteria such as anthrax
and plague as biological weapons by terrorists. Law enforce-
ment officials have the right to test for the presence of these
organisms if it is suspected that an environmental surface has
Treatment 57
Table 5.1 Recommendations from the Working Group on Civilian

Biodefense for Antibiotic Postexposure Prophylaxis During an
Outbreak of Pneumonic Plague Following a Bioterrorism Event
Choices by Patient Category Therapy Recommendations*

Adults: Preferred choices Doxycycline, 100 mg PO [orally] twice daily
for 7 days†‡
or
Ciprofloxacin, 500 mg PO twice daily for 7
days‡§
Adults: Alternative choice** Chloramphenicol, 25 mg/kg PO 4 times
daily for 7 days††
Children: Preferred choices Doxycycline: if >45 kg, give adult dosage;
if <45 kg, give 2.2 mg/kg PO twice daily
for 7 days†
or
Ciprofloxacin, 20 mg/kg PO twice daily for
7 days (maximum daily dose, 1 gm)§
Children: Alternative choice** Chloramphenicol, 25 mg/kg PO 4 times
daily for 7 days (maximum daily dose, 4
gm)††§§
Abbreviation: PO, or orally.
*Recommendations were reached by consensus of the Working Group on Civilian Biodefense and may
not necessarily be approved by the Food and Drug Administration. Although these recommendations are
intended for postexposure prophylaxis, they also can be used for treatment of plague cases in the mass
casualty setting where the number of patients is too great for all patients to receive intravenous antibiotics
and oral antibiotics must be substituted (except that treatment should be continued for 10 days instead of
7 days as for prophylaxis).
†Tetracycline can be substituted for doxycycline at a dose of 10–25 mg/kg/day divided into 2–4 doses.
‡Acceptable for pregnant women. Although fetal toxicity may occur with doxycycline use and toxic effects
on the liver in pregnancy have been noted with the tetracycline class, the Working Group recommended
doxycycline or ciprofloxacin for postexposure prophylaxis of pregnant women or for treatment of infection in
the mass casualty setting.
§Other fluoroquinolones may be substituted at dosages appropriate for age.
**Trimethoprim-sulfamethoxazole (40 mg sulfa/kg/day administered orally in two divided doses for seven
days) has been recommended for postexposure prophylaxis in children younger than eight years old and
pregnant women.
††Concentration should be maintained between 5 and 20 mcg/mL; concentrations >25 mcg/mL can cause
reversible bone marrow suppression. The oral formulation is available only outside the United States.
§§According to the Working Group, children younger than two years of age should not receive chloramphenicol.
Source: Center for Infectious Disease Research & Policy, “Plague: Current, comprehensive information on
pathogenesis, microbiology, epidemiology, diagnosis, and treatment,” http://www.cidrap.umn.edu/cidrap/
content/bt/plague/biofacts/plaguefactsheet.html (updated March 24, 2009)/html#five.
58 plague
NonToxic Disinfectant
Kills Bubonic Plague
American Biotech Labs has a disinfectant called ASAP-AGX-32
that has been approved by the Environmental Protection Agency
(EPA) for use against gram-negative bacteria, including Yer-
sinia pestis. The company was interested in determining how
well the disinfectant would actually work on Y. pestis. It did
its work at a biosafety level 3 (BSL-3) laboratory, testing the
disinfectant against a concentration of 81 million bacteria
per milliliter (mL), a dose that is 160 times greater than the
500,000 per mL that is the normal in vitro (performed in
a test tube) test dosage. Even at this higher bacterial load, all
bacteria were killed in less than 2 minutes. “The ASAP-AGX-
32 (EPA registration No. 73499-2) product has already been
approved by the EPA for use against gram-negative bacteria,
and Y. pestis is a gram-negative bacterium,” said Keith
Moeller, vice president of American Biotech Labs. “We wanted
to test the limits of the product’s capability, and we are
delighted with the results.”
Another unique aspect of the disinfectant is that it is odor-
less and colorless. “Unlike other disinfectants, the ASAP-AGX-32
can be used or sprayed around both adults and children with no
toxic effect. The product is not known to irritate the skin, eyes,
nose, or lungs,” noted Moeller.
It would seem that this product may prove to be very use-
ful in a variety of medical and industrial settings. “To date, this
product has killed every strain of every bacterium on which it
has been tested. It has received EPA approval for use against
the most deadly bacteria, including gram-negative, gram-posi-
tive and even nosocomial or hospital acquired (superbug)
pathogens. The product has been approved for use as a broad
spectrum, general use surface disinfectant in homes, hospitals,
and medical settings,” said Moeller.1
Treatment 59
been contaminated. Jim and Zachary would be in minimal

danger, since Yersinia pestis is not known to remain viable for
very long periods on most external surfaces. Some surfaces,
however, are an exception. Cells of Yersinia pestis have been
shown to live up to 6 hours on steel, 7 hours on glass, 24 hours
on polyethylene, and 120 hours on paper. Very few commer-
cial chemicals have been marketed specifically for destruction
of this organism. These types of samples must be tested at a
Reference or National LRN laboratory.
6
Prevention
There are a number of basic, commonsense methods that can be effective
in the prevention of the plague. Preventing the spread or transmission of
the plague bacterium requires that the carriers or vectors of the disease
must be controlled. This normally means that rodents and their fleas are
the targets. The fleas must be eradicated prior to or at the same time as the
rodent population is eliminated to prevent the fleas from finding a new
host to feed upon. In addition, vaccination or prophylactic use of anti-
biotics is advised for people who may be exposed to the fleas of infected
rodents. Changes in sanitary conditions that would eliminate shelter or food
for potential rodent vectors are possible long-term solutions. Killing all the
organisms and all the fleas carried by these organisms would not be practi-
cal or desirable.
Early Means of Prevention

In the past, many of the same types of remedies that were thought to be
useful in treating the plague were sometimes used to prevent it. In keeping
with the belief that the disease was spread through the air, many preven-
tive measures involved odor. It was thought that if one carried flowers or
wore a strong perfume, the odors would help keep away the disease. People
believed carrying a lucky charm could ward off the disease, although there
is no indication what that charm should consist of. Smoke from pipes
was thought to repel the disease. After the year 1350, plague patients were
placed in so-called pesthouses, where people with diseases were isolated
from the general population. Ships coming from plague-infested areas
were quarantined for 40 days until the disease could die out.
60
Prevention 61
Current Means of Prevention

Almost every brochure, magazine, medical pamphlet, or Web
site about the plague suggests the same type of advice regard-
ing prevention. To reduce the risk of contracting the plague,
food sources and possible nest sites used by rodents should
be eliminated. Every attempt should be made to rodent-proof
homes, buildings, warehouses, or feed sheds. Chemicals that
kill fleas and rodents are effective but can also cause health
risks to humans and, therefore, should usually be applied by
trained professionals. Trained professionals who can, if nec-
essary, fumigate cargoes should inspect ships and docks. It is
imperative that individuals avoid handling wild animals such
as rats, cats, rabbits, and squirrels, especially in the western
part of the United States. It is a good idea to avoid handling
any sick or dead animal. Hunters should always wear gloves.
Pets should receive weekly flea treatments with flea powder
(especially in areas where plague is present).
People should stay away from areas that are known to
harbor rats or seem likely to harbor rats. If people anticipate
that they might be exposed to rodent fleas, they should apply
a permethrin-containing repellent to clothing, shoes, and
all camping gear. Permethrin is a synthetic broad-spectrum
insecticide, similar to pyrethrin, a naturally occurring insecti-
cide. Ineffective when applied to your skin, permethrin is very
effective and durable on clothing and gear.
Insect repellants that contain N,N-diethyl-m-toluamide
(DEET) should be applied to the skin and to clothing.
However, because of toxicity, only formulations containing
approximately 30% DEET should be used. DEET products
should not be applied to infants under two months of age or to
women who are pregnant or breastfeeding. DEET is designed
for direct application to human skin to repel rather than kill
insects. DEET was developed by the U.S. Army in 1946 and
was registered for use by the public in 1957. Approximately
62 plague
140 products containing DEET are currently registered with

the EPA by about 39 different companies.
Home on the Range, Where the Ferret and

Prairie Dog Roam
In the spring of 2007, the CDC confirmed that black-tailed
prairie dogs in the Buffalo Gap National Grasslands in
southwestern South Dakota were infected with the plague
organism. These prairie dogs are the prey of the endangered
black-footed ferret. The ferret is one of the rarest mammals
in North America, and its successful reintroduction into the
area was widely hailed as an ecological success. The relation-
ship between the ferrets and prairie dogs is important because
the prairie dogs support many members of the mixed-grass
Figure 6.1 Technicians in Wind Cave National Park,

South Dakota, spray prairie dog burrows with insecticide
in an attempt to kill fleas and prevent the spread of
plague. (National Park Service)
Prevention 63
prairie ecosystem in addition to the ferret. The ferrets help to

keep the prairie dog population from exploding and destroy-
ing the grasslands.
To help increase ferret survival during this outbreak, biolo-
gists are vaccinating ferrets with an experimental vaccine. The
vaccine was originally developed for human use by the U.S.
Army. More than 40 ferrets have been captured and vaccinated
with an initial shot followed by a booster a month later. The
USGS National Wildlife Health Center in Madison, Wisconsin,
is working on an oral vaccine that can be delivered by being put
into bait, thus reducing the need to handle the animals.1
Not far from Buffalo Gap is Wind Cave National Park.
Because plague has been found within 25 miles of the park
boundary, there is concern that hikers and wildlife can be
affected. In an attempt to prevent this potential public health
threat, the staff of the National Park, working with several other
government agencies, dusted about 1,100 acres of prairie dog
burrows. The crews used ATVs to complete the work in a 10-
week period. This dusting technique has shown to be effective
in other areas of the country such as Montana.2
For those who have been exposed to animals infected with
the plague bacterium or who must be present in an area where
plague is present in the animal population, it is advisable to
begin treatment with prophylactic antibiotics. Antibiotics such
as doxycycline or tetracycline or any of the sulfonamides are
recommended.
In June 2007 an estimated 2 billion rats invaded 22 coun-
ties surrounding Dongting Lake in central China. Homes
in the area had been flooded prior to the invasion. Global
warming is also blamed for allowing rats to thrive in the
woodlands. These events caused China’s Ministry of Health
to revise an emergency response plan on the prevention of rat
plague. The plan classified plague into four categories ranging
from “extremely serious” to “ordinary” and requires relevant
departments to set up a national plague emergency command
64 plague
Bubonic Plague Hits

San Francisco 1900 –1909
On March 6, 1900, an autopsy on a dead Chinese man in San
Francisco, California, revealed organisms that resembled those
that cause plague. Despite public officials’ immediate concerns
over the potential health threat this discovery might pose, there
were political issues that hampered them from taking immediate
action. At the time, anti-Chinese sentiment was running strong.
Many whites disliked the Chinese immigrants, who were blamed
for taking jobs away from white American workers.
Upon finding plague in the dead man, San Francisco
officials decided to quarantine Chinatown, the section of the
city where most of the Chinese population lived. Both Chinese
residents and members of the business community protested,
although the businesses were worried more about the effects
that the idea of plague in their city would have on business than
about the rights of the Chinese. The city ended the quarantine,
but instead carried out inspections of each house in Chinatown.
Eventually, two more people were found to have died from
plague.
At this point, the city made a formal announcement that
there was an outbreak of plague in San Francisco. When the
governor of California refused to acknowledge the announce-
ment, the U.S. Surgeon General obtained presidential permis-
sion to enact laws to help stop the plague.
Still, the state’s officials refused to admit there was a prob-
lem, and in the meantime, additional cases of plague turned
up. Only in 1903, when a new governor came to office, was a
concentrated effort made to help the board of health put an end
to the epidemic. By February 29, 1904, when a woman from
Concord, California, died of plague, the epidemic was over—at
least temporarily. The area had counted 121 cases in the city of
San Francisco and 5 outside, with a total of 122 deaths.
A few cases of plague were reported again in 1907, but
this time, San Francisco, as well as other cities, were better
Prevention 65
Figure 6.2 Ratcatchers, such as this one in New York in 1908,

used ferrets to catch and kill rats. (Library of Congress)
prepared. Officials offered rewards for people who killed or

captured potentially infected rats. This method, which worked
well, was later used by other cities and states to help control
outbreaks of plague.3
66 plague
with close cooperation between different agencies when the

incident is considered “extremely serious.”4
Vaccination
Unfortunately, there is no vaccine against plague currently
available in the United States. A licensed vaccine was available
until the manufacturer discontinued its production in 1999 for
financial reasons. This vaccine had been used against bubonic
plague transmitted by fleabites but did not protect against
pneumonic plague. Though data about the effectiveness of
this vaccine are limited, the vaccination did seem to provide
protection for military personnel during the Vietnam War. The
vaccine caused antibody production against the F1 capsular
antigen. New vaccine development is currently aimed at using
live, attenuated strains of the bacterium (Yersinia pestis) or,
more commonly, developing vaccines that target specific mol-
ecules on the cell surface of the plague organism.
However, in January 2003, the U.S. Defense Department
granted Avant Immunotherapeutics Incorporated of Need-
ham, Massachusetts, an $8 million contract to develop an
oral vaccine against Yersinia pestis and Bacillus anthracis, the
causative agent of anthrax. This vaccine is being developed to
provide military personnel fast-acting protection against these
two potential agents of biochemical warfare. Avant will not only
design the vaccine but will also carry out all of the necessary
laboratory investigations prior to human testing.
In the March 2003 issue of Vaccine, a veterinary products
company named Heska published research about a vaccine to
prevent the spread of plague in animals. The company had
previously worked with the U.S. Geological Survey’s National
Wildlife Health Center on an experimental vaccine to prevent
plague in prairie dogs. The new vaccine uses the same tech-
nique as the vaccine used to immunize mice against plague.
The research is designed to develop a vaccine that would be
delivered orally to wild animal populations by embedding it in
food left as bait in areas frequented by rodents.
Prevention 67
Figure 6.3 Vaccine immunity.

68 plague
Vaccines Outside the United States

Although it is not available in the United States, a vaccine
against bubonic plague is manufactured and is available in
some countries, including Australia. The plague vaccine can
be given to both adults and children. For adults and chil-
dren older than 12 years of age, two doses of the vaccine are
needed and are given one to four weeks apart. Children under
12 years of age require three doses of the vaccine spaced one
to four weeks apart. To achieve the possibility of full protec-
tion, all doses must be received. It takes the body several
weeks to develop a sufficient supply of antibodies to provide
protection. Even then, the vaccine cannot ensure 100 percent
protection against the disease. People who live in areas where
plague is active and widespread should receive a vaccine
booster shot every six months. Other groups of individuals
who should consider vaccination include people who work
in the laboratory or in the field with the plague organism,
including veterinary doctors and staff working with poten-
tially infected animals. Since 2003, a number of initiatives
have been undertaken to develop vaccines against the plague.
These will be discussed in Chapter 9.
7
The Problems of
Antibiotic Resistance
Antibiotics are chemicals produced by living organisms, usually fungi or
bacteria, that destroy or inhibit other microorganisms or their ability
to reproduce. Since the mid-1950s, an increasing number of microbes
have shown antibiotic resistance, and are no longer killed or inhibited
by particular antibiotics. The initial relief that came from the ability
to conquer disease through use of antibiotics such as penicillin and
streptomycin has become muted as more microbes have found ways to
neutralize or inactivate the antibiotics. Fortunately, antibiotic resistance
in Yersinia pestis continues to be rare. Development of widespread anti-
biotic resistance would be a significant threat given that antibiotics are
used for both plague treatment and for prevention of human-to-human
transmission. The National Academy of Sciences has suggested that it
may cost as much as $30 billion annually to treat antibiotic-resistant
infections.
Microorganisms have lived in close proximity to each other in the soil and
water for millions of years. Often, they compete for the same scarce resources.
To succeed in such a competitive environment, microorganisms find bio-
chemical means of destroying or inactivating chemicals produced by other
organisms. This ongoing process in which one organism produces destructive
chemicals and another finds ways to destroy the first organism is nature’s way
of maintaining a balance among the microbes in the soil and water.
The two main issues to address regarding antibiotic resistance are why
and how it occurs.
69
70 plague
Why Resistance Occurs

Simply put, antibiotic resistance develops due to the abuse,
misuse, and overuse of antibiotics. For example, antibiotics
are ineffective against viruses, yet patients often press their
doctors to prescribe antibiotics for viral maladies, including
colds or influenza. If antibiotics are taken for a viral infection,
they destroy some of the helpful bacteria in the intestines.
Bacteria, both “good” and “bad,” are in constant competition
in the intestines. Destruction of the “good” bacteria provides
opportunity for the unfettered growth of “bad” bacteria.
Another reason antibiotic resistance occurs is the failure
of the patient to follow instructions. When antibiotics are
prescribed, the patient is directed to take all of the antibiotics
provided. Often, patients stop taking antibiotics as soon as
they start to feel better, even though there are still bacteria in
their bodies. By not completing a full course of antibiotics,
only the least resistant of the offending bacteria are killed off,
leaving the most resistant alive. These more resistant bacteria
survive and reproduce, which means that the next time the
person is infected, it will take a higher dosage or a different
antibiotic to kill the same bacteria.
Microorganisms also can become resistant to antibiotics
when antibiotics are used in low doses in livestock and agri-
culture. Antibiotics are often mixed with animal feed. The
amounts are too small to be used for treating a disease, but
they do destroy the least hardy bacteria. The most resistant
bacteria survive. Part of the rationale for giving antibiotics
to livestock is to keep the animals healthy and allow them to
grow rapidly without competition from internal parasites in
the form of intestinal bacteria. Antibiotic residues are also
often found on fruits and vegetables that have been sprayed
to reduce premature decomposition. If we are not careful
about washing fruits and vegetables before we eat them, we
may kill off some of our useful bacteria, allowing the more
resistant and harmful organisms to survive. On June 3,
2002, the New York Times documented the discovery of the
The Problems of Antibiotic Resistance 71
antibiotic chloramphenicol in shrimp imported from Asia.

Agricultural use of this antibiotic is banned in the United
States because it has been shown to cause problems such as
childhood leukemia.
Finally, antibiotics may be available without a prescription
in some countries. If a person taking an antibiotic is not aware
of the limitations and potential problems that can occur when
some bacteria survive antibiotic treatment, an environment
may be created in which resistant organisms not only survive
a course of antibiotics, but also grow more and more resistant
over time.
How Resistance Develops

Microorganisms have an amazing ability to adapt very rap-
idly to new and changing environmental conditions. They
often have a reproductive rate that doubles their numbers in
minutes. Both Escherichia coli and Staphylococcus aureus can
double their numbers every 12 to 20 minutes under optimal
conditions.
Bacteria have genetic material that is extremely flexible. It
consists of a single chromosome and a number of small chunks
of DNA called plasmids, which look like miniature chromo-
somes. Plasmids contain a limited number of genes that are
often genetic codes for enzymes and other proteins that provide
resistance to one or more antibiotics.
There are a number of ways that bacteria can develop
resistance to antibiotics. One of these methods is through
mutations of their genetic information or DNA. A mutation
is a change in the genetic information of a cell or virus. A
single mutation can spread through a population of bacteria
in a matter of hours. If that mutation provides a way for
bacteria to survive in the presence of a particular antibiotic,
the genetic change will soon be found in millions of newly
resistant bacteria. When bacteria die, other bacteria often
scavenge the DNA of the dead microbe and incorporate it
into their own genetic programs. Called transformation, this
72 plague
new information may contain genetic codes for inactivating

or neutralizing various antibiotics.
Some bacteria can exchange copies of plasmids. A copy
of a plasmid is passed through a protein tube called a pilus
into another bacterium, during a process called conjugation,
making it possible to exchange genetic information between
live bacteria (Figure 7.1).
In a sense, this was the first information highway; it has
been active for millions, perhaps billions, of years. Some of this
new genetic information may provide the recipient bacterium
with a competitive advantage in its environment.
Bacteria often are infected by specific viruses. As a virus
infects one bacterium, it takes over the cell and forces the bac-
terium to produce and assemble new virus parts. As the new
virus is constructed, it may incorporate some of the bacterial
DNA into its own genetic program. When the new viruses
infect other bacteria, they may leave some of the incorporated
bacterial DNA in the newly infected bacterium. This process is
called transduction and, like the others mentioned earlier, this
method provides new genetic information to a bacterium that
may allow it to become resistant to one or more antibiotics.
Bacteria have evolved a number of mechanisms at the
molecular level that allow them to resist antibiotics.
• Often, an antibiotic must attach to a particular structure

such as the cell wall or a protein receptor in the cell mem-
brane. If the bacterium changes the target molecule in
some way, the antibiotic will not be able to attach to the
bacterium and will be ineffective.
• Some bacteria take the antibiotic into their cells and

surround it with a membrane of proteins. This effectively
prevents the antibiotic from interfering with a biochemical
process or locking on to a receptor molecule.
• Certain bacteria produce chemicals such as enzymes that

inactivate or destroy the drug. One example is gonorrhea
Figure 7.1 Bacteria can transfer antibiotic resistance in three ways.

In the process of conjugation (a), a bacterium injects its mutated
genes into another bacterium through a special connection. A virus
can also give its resistance genes to a new bacterium in a process
known as transduction (b). Resistance genes can also be integrated
into a new bacterium when another bacterium dies, in a process
called transformation (c).
74 plague
microbes that produce a chemical called penicillinase,

which neutralizes penicillin. These microbes are designated
penicillinase-producing Neisseria gonorrhea (PPNG).
• Other species of bacteria may contain structures,

such as a capsule, which keep the antibiotic from
penetrating into the cell.
• Some bacteria have molecular pumps called efflux

systems that actively remove antibiotics or other unwanted
chemicals from the cell.
Current Research
A group of researchers at Old Dominion University in Nor-
folk, Virginia, has developed a way to study the efflux mecha-
nisms of specific gram-negative bacteria. Efflux systems are
designed to pump out of the bacterial cell substances such as
antibiotics that the cell considers harmful. Dr. X. Nancy Xu
and her colleagues from the department of chemistry and
biochemistry combined two types of microscopy with a fluo-
rescent dye called ethidium bromide. Their method allows
for real-time study of individual live cells for an extended
period.
The group found that individual cells vary greatly in the
rate at which they pump out the antibiotics. Since the usual
study method is to look at what happens with the majority of
cells, being able to see individual cell differences will allow for
earlier detection of the resistance. The short-term goal of the
group is to understand the nature of multidrug resistance in the
bacteria so that new therapies and drugs that target the pump
mechanisms may be developed. “The purpose of this under-
standing of multidrug resistance is to be able to use a very low
dose of drugs, for fewer side effects,” said Dr. Xu. Xu suggested
that the group also hopes to use this knowledge to construct
and bioengineer an efflux pump that could possibly sense and
deliver drugs.1
The National Institute of Allergy and Infectious Diseases

(NIAID) is a component of the National Institutes of Health
(NIH). A major part of its job is to support research efforts
to prevent, diagnose, and treat infectious and immune-medi-
ated illnesses. NIAID supports research to study the molecular
mechanisms responsible for drug resistance and to develop new
chemical interventions for disease treatment and prevention.
NIAID spends $200 million annually on antimicrobial resis-
tance research.2
Research using gene-sequencing techniques can identify
the critical molecules involved in microbial reproduction. These
molecules may then serve as targets for new drugs. Research
conducted so far in the area of drug resistance has led to:
• The discovery of methods that will make it possible to

reverse resistance to antibiotics.
• An understanding of the genetic reasons why some

parasites become resistant and the ability to recognize
the organisms that are, in fact, resistant.
• New molecular level mechanisms and tools that make

it easier to recognize those species that are resistant to spe-
cific drugs.
• New drugs being created to combat the drug-resistant

strains of Plasmodium, the organism responsible for the
disease malaria.
An editorial by David Dennis and James Hughes, both

from the CDC, appeared in the September 4, 1997, issue of
the New England Journal of Medicine. In the editorial, Dennis
and Hughes addressed the problems associated with emerg-
ing infections, particularly with respect to growing antibiotic
resistance in the plague bacillus and other bacteria carried by a
variety of vectors such as fleas, ticks, flies, and mosquitoes. They
suggest that the first line of defense against these emerging
76 plague
An Antibiotic-resistant
Plague Organism
In 1995, a 16-year-old boy in Madagascar was diagnosed with
bubonic plague. The particular strain isolated from the boy was
identified as 17/95 biotype orientalis. This particular strain
was resistant to eight different antibiotics, including ampicillin,
chloramphenicol, kanamycin, streptomycin, spectinomycin, the
sulfonamides, tetracycline, and minocycline. Resistance to most
of these antibiotics was the result of the bacteria being able to
produce chemicals that neutralized or inactivated the antibiotics.
Genetic analysis of the plasmid DNA found in the 17/95
strain showed that the plasmid contained fragments of
another plasmid normally found in Escherichia coli, a normal
intestinal bacillus. This raises the question of how and where
the Y. pestis bacteria acquired the E. coli plasmid. There
are a number of places where both microbes would be found
together, including inside and outside the mammalian host.
Of greater concern is the fact that plasmids are transferable
between species, increasing the likelihood that more multi-
drug-resistant Y. pestis will appear again.
In October 2002, the question of how and where Yersinia
acquired the E. coli plasmid appeared to be answered. A group
of researchers showed that Yersinia acquires antibiotic-resistant
plasmids from E. coli by horizontal transfer within the midgut
of the flea. It is clear from the article that close physical contact
between the E. coli and the Y. pestis plasmids leads to high-
frequency conjugative genetic exchange. The article suggests
that this may have been the source of the antibiotic-resistant
strain isolated from the boy in Madagascar.
diseases would be a system of domestic and global surveillance

and response. Dennis and Hughes further indicated that there
are four basic requirements for such a system. The first would
be the ability to detect clusters of new and unusual diseases

and syndromes. Second would be the capability to identify and
characterize the infectious agents in a laboratory setting. Third
is the ability to analyze and distribute information quickly and
globally. Fourth would be the development of feedback systems
that would cause both investigative and control responses.
Hughes and Dennis suggest that each of these four components
is “critical in confronting the emergence of plague and the
potential for the emergence of drug-resistant disease.”
The editorial was written in response to another article also
appearing in the same issue. The article, entitled “Multidrug
Resistance in Yersinia pestis Mediated by a Transferable Plasmid,”
was written by Marc Garlimand and six of his colleagues. The
article points out that plague is now considered a reemerging
disease and, since 1994, has appeared in epidemic numbers in at
least three countries. The plague organism is normally suscep-
tible to a number of antibiotics including streptomycin, chlor-
amphenicol, tetracycline, and the sulfonamides.
As explained at the beginning of this chapter, microbes
live in close proximity to each other in a variety of habitats
including the intestinal areas of many animal species. Since
2002, there has been a rapid worldwide emergence of MDR
(multiple drug-resistant) bacterial pathogens in a number of
animals used as food sources by humans. The most common
symptom caused by eating these contaminated food sources
is a self-limited gastroenteritis that normally resolves itself
without the use of antibiotics. Because multiple drug resis-
tance information is located on mobile plasmids, there is an
excellent chance that MDR genetic information can be passed
from foodborne pathogens to more virulent human patho-
gens, including Y. pestis. The mechanism of that transfer
could be any of those mentioned in the chapter. Such genetic
transfer would constitute a serious public health threat.
The plasmid-positive strains were found in bacteria associ-
ated with beef, chicken, turkey, and pork, and were found in
78 plague
samples from the following states: California, Colorado, Con-

necticut, Georgia, Maryland, Minnesota, New Mexico, New
York, and Oregon. MDR Salmonella and E. coli have been found
in droppings from wild geese, raising the possibility that wild
animals might be able to spread MDR far beyond the livestock
where it originated.
8
Concerns for the Future
There are two major interrelated concerns that seem to override all others
when it comes to the plague: (1) the concern that new, antibiotic-resistant
strains of the organism will become common; and (2) the concern that the
plague organism might be used as a weapon of bioterrorism.
Evolution of Resistant Strains

Increasing antibiotic resistance is a major problem in dealing with dis-
ease organisms such as Yersinia pestis. One of the major reasons that Y.
pestis survives in the environment of the flea’s midgut is because it has
an enzyme called phospholipase D (PLD). This enzyme, formerly called
Yersinia murine toxin, gives the microbe resistance to a product in the
blood plasma of the flea that would otherwise destroy the bacterium.
It is still not known exactly what molecular mechanisms provide this
protection. Yersinia pestis acquired the gene for production of PLD
from either an unrelated bacterium or a simple nucleated organism
such as a protozoan. Once Y. pestis had acquired this gene, it had a new
means of transmission. The bacteria transformed from an organism that
caused mild stomach illness through contaminated food and water to a
flea-borne carrier of a life-threatening disease. Research at Rockefeller
University in New York has provided at least a partial answer as to how
Yersinia protects itself from the host’s immune system. The researchers
found that Yersinia contains a protein—whose shape is similar to that of
an apparently unrelated mammalian enzyme—that blocks a host cell’s
ability to change shape and move. Since many of the immune system
cells carry out phagocytosis, which requires both movement and shape
changes, a loss of these capabilities would impair the ability of cells of
79
80 plague
Global Outbreak Alert and

Response Network
In April 2000, the World Health Organization (WHO) set up
a meeting between representatives of technical institutions,
various organizations, and networks involved in surveillance
and response to global epidemics. The participants recognized
the need to provide a global network to identify and deal with
the threats posed by epidemic-prone and emerging diseases.
This newly formed network developed a set of Guiding Principles
for International Outbreak Alert and Response. In addition,
they have developed laboratory rules and regulations that pro-
vide standardization in various areas such as research, com-
munications, security, and clinical management.
The Global Outbreak Alert and Response Network uses
technical and other resources from the scientific groups within
WHO. In addition, it has partnered with United Nations
organizations such as UNICEF, the Red Cross, and interna-
tional humanitarian organizations worldwide. This network
works towards providing security to global health by:
• Combating the international spread of outbreaks.
• Ensuring that appropriate technical assistance reaches

affected states rapidly.
• Contributing to long-term epidemic preparedness and

capacity building.
Since its inception, the network has been involved in projects

in at least 40 different countries from Afghanistan to Uganda,
dealing with diseases including yellow fever, influenza, Ebola
fever, and Rift Valley fever.
the immune system to track down and “eat” foreign invad-

ers, the researchers explained. These results provide insights
that could lead to new strategies for fighting the organism.
Concerns for the Future 81
“Yersinia injects several virulence factors into its host,” said

C. Erec Stebbins of Rockefeller University. “If we can discover
which ones are critical, we might identify the pathogen’s
Achilles heel—an attractive target for antibacterial or anti-
virulence compounds. It is becoming increasingly clear that a
common strategy used by bacterial pathogens to manipulate
host cell biology is the mimicry of their own biochemical
processes,” Stebbins said.1
History of Plague as a Weapon

It has been suggested that plague served as the original bio-
logical weapon in wartime. History records that the Tatars
were attempting to capture the Italian-controlled city of
Kaffa on the shore of the Black Sea in 1347. Plague broke
out in the Tatar camp. The defenders of Kaffa resisted until
the Tatars began to hurl the bodies of their own dead over
the walls and into the city. The Tatars had been dying of the
plague by the thousands, and now, so did the defenders of
the city. Those who eventually escaped the city took to their
ships and headed for ports in the Mediterranean, carrying the
plague with them. The city of Kaffa became uninhabitable,
and the Black Death quickly spread throughout Europe.
During World War II, the Japanese were known to have
dropped fleas infected with plague organisms over populated
areas of China. A number of outbreaks of plague resulted. After
World War II, both the United States and the Soviet Union
used their biological weapons programs to find new techniques
and delivery methods for a variety of microbial agents, includ-
ing plague. Both countries were successful in finding ways to
aerosolize Yersinia pestis, which increased its usefulness as a
potential biological weapon.
Obviously, this ability to spread the organism in an aerosol
form has led to concern that terrorist groups or nations might
acquire and use it. Scientists who defected from the former
Soviet Union suggested that an antibiotic-resistant strain of
Yersinia pestis had been developed.
82 plague
In 2001, the complete genome of the plague microbe was

sequenced. Julian Parkhill, leader of the sequencing team,
suggested that the sequence would be critical in helping to
design antibiotics and vaccines that may be used against this
disease organism. Another member of the group, Rick Tit-
ball, is leading a team that has produced a vaccine that is cur-
rently in clinical trials. Titball believes that “the information
available [about the genome] is of much greater advantage
to people defending against biological warfare than to those
intending to use it.”2
Plague as a Bioterrorist Agent

The Centers for Disease Control and Prevention (CDC) has
placed plague in Category A, which is the highest-priority cat-
egory for an agent that could be used for bioterrorist activity.
Plague meets the criteria set up by the CDC, which are that:
• It is easily disseminated or transmitted from person

to person.
• It results in high mortality rate and has the potential for

major public health impact.
• It might cause panic or social disruption.

• It requires special action for public health preparedness.
The Working Group on Civilian Biodefense prepared a
consensus statement that concluded:
Given the availability of Y. pestis around the world, capac-

ity for its mass production and aerosol dissemination,
difficulty in preventing such activities, high fatality rate
of pneumonic plague, and potential for secondary spread
of cases during an epidemic, the potential use of plague
as a biological weapon is of great concern.3
In 1970, the WHO issued a report suggesting that up
to 36,000 deaths and more than 150,000 incapacitating ill-
nesses would result from the airborne release of 50 kilograms

(approximately 110 pounds) of dried powder containing
Yersinia pestis in a country such as the United States. These
numbers represent only direct impacts and do not take into
account the number of secondary infections and deaths that
would result from subsequent person-to-person contact.
NIAID Research
Because bioterrorism continues to be a real concern for the
United States, the National Institute for Allergy and Infectious
Diseases (NIAID) and other agencies have accelerated microbial
research and development of diagnostic, preventive, and treat-
ment methods. Microbial genomics, the study of the totality
of genetic information found in an organism, has become an
important part of this overall approach. The complete collection
of an organism’s genetic information is known as its genome.
Understanding an organism’s genetic program may aid in under-
standing how an organism carries out its biochemical and physi-
cal processing and operates as a complex biological system.
This genetic information can be used to develop gene-
based diagnostic and sampling tests to quickly detect dangerous
germs and assess their susceptibility to different types of treat-
ment. Genomes also provide molecular fingerprints of different
strains of a given microbe, thereby enabling investigators to
better track future outbreaks to their source. Current long-term
research of NIAID includes:
• Identifying genes in the Y. pestis bacterium that infect the

digestive tract of fleas and researching how the bacterium
is transferred to humans.
• Studying the disease-causing proteins and genes of Y. pestis

that allow the bacterium to grow in humans and how they
function in human lungs.
NIAID is also working with the Department of Defense,

the CDC, and the Department of Energy to:
84 plague
• Develop a vaccine that protects against inhalationally

acquired pneumonic plague.
• Develop promising antibiotics and intervention strategies

to prevent and treat plague infection.
In 2002, NIAID released its “Biodefense Research Agenda

for CDC Category A Agents.” The bubonic plague organism
was high on the list of the greatest bioterror threats.
Hopes for developing a viable vaccine have led to a num-
ber of collaborations between groups, companies, and nations.
In 2005 the United States, Canada, and the United Kingdom
signed an agreement to work together to develop a vaccine for
plague. The United States and the United Kingdom have each
developed vaccines that were being tested in clinical trials. At
the end of 2005, they selected a vaccine to continue on the test-
ing trail.4
In 2006, the Biodesign Institute at Arizona State University,
Icon Genetics (Halle, Germany), and the U.S. Army Medical
Research Institute for Infectious Disease demonstrated a vac-
cine whose components had been grown in tobacco leaves as
the biological factories. Animal testing showed that the vaccine
protected the animals against an aerosol form of the plague
organism.5
And in 2007, Ichor Medical Systems was awarded a two-
year contract valued at more than $2.3 million by the Defense
Threat Reduction Agency (DTRA). Ichor is working with the
Biological Defense Research Directorate (BDRD) of the Naval
Medical Research Center (NMRC) in Rockville, Maryland, in
the development of a DNA vaccine for anthrax and plague.6
Cautionary notes
Plague has already been classified as a reemerging disease.
Although its impact today is less dramatic than its past history
it is still a severe problem. The Wildlife Conservation Society
(WCS) has spotlighted plague as one of the 12 most deadly
diseases capable of causing pandemics because of natural

infections stimulated by climate change. “Plague is spread by
rodents and their fleas and alterations in temperatures and
rainfall are expected to change the distribution of rodent
populations,” said Steven Sanderson, WCS president.7
In a November 2008 article entitled “Study of Ancient and
Modern Plagues Finds Common Features,” three prominent
NIAID researchers discuss disease emergence. “There appear to
be common determinants of disease emergence that transcend
time, place and human progress,” says NIAID director Anthony
S. Fauci, M.D., one of the study authors. International trade
and troop movement during wartime, poverty, lack of political
will, and changes in climate, ecosystems and land use are some
of the determinants the article mentions. “A better understand-
ing of these determinants is essential for our preparedness for
the next emerging or reemerging disease that will inevitably
confront us,” says Dr. Fauci.
“The art of predicting disease emergence is not well devel-
oped,” says David Morens, M.D., another NIAID author. “We
know, however, that the mixture of determinants is becoming
ever more complex, and out of this increased complexity comes
increased opportunity for diseases to reach epidemic propor-
tions quickly.”
Our ability to understand and, more importantly, to pre-
dict when, where, how and why disease-causing microbes cause
their diseases and how they make the jump from animals to
humans requires continuing research. Only by looking at the
broad framework as well as the specific pieces can scientists
effectively combat these disease organisms.”8
9
Hopes for the Future
Techniques originally used to help analyze the human genome may soon be
used as tools to decipher the DNA of Yersinia pestis, investigate how anti
biotic resistance develops, and make earlier detection possible. Researchers
are also looking at ways to investigate a number of host-pathogen interac-
tions, including how pathogens use host cell membrane proteins to enter
host cells.
PCR (polymerase chain reaction)-based plasmid typing has become
a standard method to screen multiple cultures to identify specific genetic
sequences. PCR assays could also be used to look for antibiotic resistance
plasmids in foods and within the stages of the food production process.
Conceivably, such test procedures could prove useful for detecting these
plasmids in biothreat organisms including Y. pestis.1
Detecting Bacterial DNA Sequences

Antibiotic resistance in bacteria is an inherited characteristic, but
attempting to analyze all of the DNA of all of the organisms present
in an infection is not practical. A new method is under development
at the University of Rochester Medical Center in Rochester, New York,
that detects the presence of specific DNA sequences. Certain portions
of DNA molecules take particular shapes based on their ability to find a
complementary information sequence at the end of the DNA molecule.
Once the DNA sequence that represents antibiotic resistance is found
in one bacterial species, that sequence can be used as a model to find
the same sequence in other bacteria. A fluorescent molecule is attached
to one end of the DNA strand and can be used as a molecular beacon
when bacteria suspected of being antibiotic resistant are checked on
86
Hopes for the Future 87
Microarrays
Microarrays, also called DNA chips, gene chips, DNA micro
arrays, or gene expression microarrays, represent a blending
of computer technology and DNA. Researchers cover a small
glass chip with hundreds to thousands of fragments of DNA.
Each of these fragments represents a different gene within the
cell being studied. By adding a fluorescent molecule to the
fragments, they can be made to light up when they come into
contact with a complementary gene. This tells scientists about
the activity level of the genes in question. Microarrays make it
possible for researchers to determine which genes are being
activated and under what conditions. These microarrays are
being used to try to understand the genetics involved with how
microorganisms respond to drugs, how they respond to different
environmental conditions, and how they are able to infect
different kind of host cells. This new technology gives scien-
tists the opportunity to test many genes simultaneously, thus
speeding up the process of detecting change within the cell.2
a slide. The hope is that a single microarray or DNA chip

would be able to test different species as well as different
strains within a species to determine if they are resistant to a
specific antibiotic.
Discovering How to Disable

Bacterial Weapons
In May 1999, researchers announced that they had found a
way to prevent a number of bacteria from causing disease.
It is hoped that the findings, published in the journal Sci-
ence, can be used to develop a new generation of vaccines
and antibiotics. The researchers reported that they had
identified a “master switch” controlling the production of
many chemicals that bacteria use to cause infection. When
88 plague
scientists knock out the switch, the bacteria are no longer

capable of causing disease. It seems that the master switch
for pathogenic bacteria, such as Vibrio cholerae (cholera),
Yersinia (plague), Salmonella (typhoid fever), and Shigella
(dysentery), is the same. Treatment of these bacterial infec-
tions, as well as others, may be affected by this discovery. It is
also hoped that this discovery can be used in the fight against
newly emerging, drug-resistant pathogens.
Michael Mahan and his colleagues used a mutated strain
of Salmonella with the master switch always on. This allowed
researchers to discover all the tricks the organisms use for
getting past the stomach and intestines and into organs and
tissues. “This [knowledge of how to stop organisms from
invading] has two important consequences,” Mahan states.
“The bacteria are completely disabled in their ability to cause
disease, and these crippled bacteria work as a vaccine since
they stimulate immune defenses to defend against subse-
quent infections.”3
Researchers at the University of Illinois and the University
of Massachusetts at Amherst have developed a method that
causes a bacterium to reprogram its genetic information and
cause its own death. “The basic idea is for an antimicrobial to
target something in a bacterium that, in order to gain immu-
nity, would require the bacteria to kill itself through a suicide
mutation,” said Gerard Wong, a professor of materials science
and engineering, of bioengineering and physics at the Univer-
sity of Illinois.
The researchers have been working with a class of anti-
microbial molecules that causes holes to be created in the cell
membrane of the bacterium. A synthetic “hole punching” anti-
microbial depends on the presence, in the membrane, of a lipid
molecule called phosphoethanolamine (PE). This molecule is
found in high concentrations within gram-negative bacterial
membranes. PE lipids are used to kill the bacteria, but without
the lipids the bacteria would die. “It’s a catch-22,” Wong said.
“Some mutations bacteria can tolerate, and some mutations

they cannot tolerate. In this case, the bacteria would have to go
through a mutation that would kill it, in order to be immune
to these antimicrobials. The antimicrobial reorganizes PE lipids
into holes in the membrane,” explained Wong. “The perforated
membranes leak, and the bacteria die.”
As the number of emerging pathogens increases, and many
become more resistant to the available antibiotics, it becomes
critically important that we “more fully understand how our
molecular ‘hole punchers’ work, [so that] we can look for
similar ways to make antimicrobials [to which] bacteria cannot
evolve immunity.”4
Deciphering the DNA of Yersinia pestis

Determining the sequence of the bubonic plague organism
will hopefully lead to the design and development of new anti-
biotics and vaccines. In this case, we will also learn a great deal
about how infectious bacteria have evolved over time. Accord-
ing to researchers from the Yersinia gene sequencing team,
the plague organism descended from an intestinal organism,
Yersinia pseudotuberculosis, which two thousand years ago
gave you a mild tummy ache. One reason for the rapid evolu-
tion of Y. pestis may be its ability to shuffle segments of its
chromosome, an activity common among pathogens. Yersinia
pestis also carries genes for insecticidal toxins that are now
deactivated but may have aided its move into the fleas. The Y.
pestis organism contains about 150 pseudogenes — repeating,
gene-like sequences of DNA that are no longer active in the
organism. These sequences may eventually be lost from the
organism completely.
The Yersinia pestis genome was added to the Comprehen-
sive Microbial Resource (CMR) in December of 2002. The
CMR is a free Web site used to display information on all of
the publicly available, complete prokaryotic genomes.5 Since
2002 a number of additional studies have provided valuable
90 plague
information about the role of several genetic sequences within

that genome.6
How Bacterial Cells Communicate

Biologists have long speculated that bacteria are able to com-
municate with each other and their environment by releasing
and then detecting various types of chemicals. This activity
is a form of molecular census-taking and is usually called
quorum sensing. Evidence exists that indicates more than
70 different types of organisms, including Yersinia pestis, are
engaged in this activity. According to researcher Rong-guang
Zhang, the quorum-sensing process signals bacteria to create
biofilms , or mats of bacterial cells over a solid surface.
The researchers used the Structural Biology Laboratory
at Argonne National Laboratories to determine the molecular
structure of a protein called TraR. This key protein seems to
act as a relay that senses chemicals called pheromones. Once
the bacterial cell senses these molecules, it activates specific
genes that allow it to create biofilms. Knowing the structure
of this protein allows scientists to pursue two different ave-
nues of research. They may be able to find or create drugs that
would block the chemical signals and thus prevent formation
of biofilms. Conversely, they could stimulate the production
of biofilms for useful projects such as water filtration.
New Antibacterial Drugs

Researchers at the Wistar Institute in Philadelphia have
identified and isolated a group of insect peptides (short pro-
teins) that attack specific molecules in bacteria. Insects lack
an immune system and have devised strategies to eliminate
bacteria and other germs. The insect host may use peptides
to create holes in bacterial membranes, or the peptides may
bind to target sites within the bacterial cells causing death
in some poorly understood way. Working with a European
sap-sucking insect, Pyrrhocoris apterus, scientists identified

the antimicrobial peptide called pyrrohocoricin. The target of
this molecule is another protein called DnaK whose job is to
identify and correct the shape of proteins that have folded up
incorrectly. DnaK is a “heat-shock protein” and, when it is
bound by the pyrrhocoricin, DnaK is unable to complete its
work of repairing misshapen proteins. This usually leads to
the death of the bacterium. The insect peptide does not bind
to mouse or human equivalents of DnaK and thus is not toxic
to humans.
Nanoparticles Can Be Used to Kill Bacteria

Researchers at Kansas State University have developed
nanoparticles made of magnesium oxide to kill various bacte-
ria, including bioterorrism agents such as anthrax and E. coli,
in about five minutes. Kenneth J. Klabunde and his team have
shown that these particles have an electrical charge opposite
to that of the electrical charge on bacteria. The opposite
charges attract the particles to the bacteria. The sharp edges
of the particles penetrate even endospores of anthrax bacte-
ria. Because the particles are alkaline rather than acidic, they
can penetrate bacterial cell walls. Nanoparticles are solid
rather than gaseous or liquid, which would allow them to be
placed in air filtration units or sprayed like a powder.
Research continues into the use of nanoparticles for direct
killing of microbes as well as use as a means of drug delivery
and a means of detection of these pathogenic microbes. An
article by Xuefei Huang and colleagues, entitled “Magnetic
Glyco-Nanoparticles: A Unique Tool for Rapid Pathogen
Detection, Decontamination, and Strain Differentiation,”
was published in the Journal of the American Chemical Soci-
ety. It tells of a “magnetic glyco-nanoparticle (MGNP),” a
unique compound that combines magnetic nanoparticles
with sugars.7
92 plague
Many scientists worry that silver nanoparticles may be

potentially harmful or at least not as benign as people once
believed. Silver has long been used to kill microbes, but it kills
good microorganisms along with the bad. Silver nanoparticles
are already present in many consumer products. Many of the
silver particles are showing up in drinking water supplies with
the potential to kill beneficial bacteria. “Nanoparticles are very
small, and they are interacting with the bacteria and ruptur-
ing the cell wall,” says chemist George John of The City Col-
lege of New York and lead author of a study published in the
journal Nature Materials. This rupturing kills the bacteria, he
explains.8
New Diagnostic Tests

The ability to detect the plague organism rapidly would greatly
reduce the number of deaths and the likelihood of transmission
among people. Scientists from the Pasteur Institute in France
Figure 9.1 The dipstick diagnostic test for plague

provides reliable results in 15 minutes. (© Institut Pasteur)
and the Ministry of Health in Madagascar developed a simple

test, called a dipstick test, that provides reliable results within
15 minutes. The dipstick test recognizes a unique substance
called F1 antigen, which is found in the blood and infected
fluid of buboes. By rapid detection of pneumonic plague, more
infected patients will be able to get rapid treatment. Since its
development in 2002, the dipstick test has become the major
rapid diagnostic technique used worldwide.
DRUG DEVELOPMENT
The Science and Technology Review of Lawrence Livermore
National Laboratory details the use of a new method called
accelerator mass spectrometry. This analytical technique
uses very high voltages, usually in the mega-volt range, to
accelerate negative ions to identify the chemical composi-
tion of a compound or sample. Yersinia pestis is one of the
four disease models the laboratory will use to find broad-
spectrum anti-infective drugs that can target agents, such as
plague or Hantavirus, which may be modified or engineered.
Scientists could identify both common and unique factors in
the immune response—a critical process for fighting infec-
tion—based on research on four particular disease models
including plague, Francisella tularensis (tularemia), Brucella
abortus (brucellosis), and Hantavirus.
The Lawrence Livermore Laboratory will be working with
Trius Therapeutics a San Diego–based biotech company that
recently was granted a five-year $28 million contract from the
NIH to develop novel antibiotics against some possible bioter-
rorism microbes. This work is at a very early stage of develop-
ment. The grant comes from the National Institute of Allergy
and Infectious Diseases (NIAID), a unit of NIH.9
Drug development often requires 6 to 8 years of laboratory
research, followed by the use of the drug by laboratory animals.
The difficult part is to find a dosage that will work in humans
while testing research animals. If the animal test results seem
94 plague
promising, Phase I clinical trials follow. Phase I testing typi-

cally involves 10 to 20 healthy human subjects who volunteer
to participate. They are given the new drug at clinical doses
to evaluate its safety, determine a safe dosage range, and help
identify its possible side effects. Subsequent Phase II and III tri-
als involve a larger number of human subjects, who are patients
diagnosed with the specific illness that scientists hope the drug
will help treat or cure. It is not unusual for the process to fail
at the point where Phase I clinical trials begin because research
has repeatedly shown that humans and animals metabolize
many substances differently.10
New Vaccine Trials

Currently in clinical trials is a new type of vaccine for the
plague. At this point, vaccines do not provide 100 percent
protection against the inhaled forms of the plague. Nose
drops and nasal sprays of biodegradable microspheres con-
taining antigenic subunits F1 and V are being tested on mice.
This approach seems to protect the animals from inhaled
and injected forms of the plague organism. Testing in larger
animal models and humans will follow. This type of a vac-
cine has the advantage of being administered easily and to
large numbers of people quickly. Another vaccine possibility
involves the use of monoclonal antibodies against the V and F1
antigens of Yersinia pestis. Whether given alone or in combi-
nation, mice were protected against bubonic and pneumonic
plague. The antibodies worked well whether given prior to
infection or within 48 hours after infection.
In June 2008, DynPort Vaccine Company (DVC) was
informed it would continue development of a recombinant
plague vaccine candidate called rF1V. Vaccine development
includes possible licensure by the U.S. Food and Drug Admin-
istration (FDA). The vaccine is currently in Phase II clinical
trials.11
Scientists in many areas of the country, working for uni-

versities and companies, are involved in vaccine development
to fight the plague. In July 2008, professor Henry Daniell and
his team from the University of Central Florida reported that
they had developed a vaccine whose early results indicate that
it will be highly effective against the plague. The vaccine can be
taken orally or by injection. Having a pill form of vaccine allows
for a more rapid distribution and removes the need for special
skills or sterile needles. Human trials are still needed but animal
studies suggest that the vaccine will work for both the bubonic
and pneumonic forms of the plague.12
In August 2008, researchers from the Pasteur Institute in
Paris reported in the journal Infection and Immunity that they
have also developed a live oral vaccine. They used a less virulent
ancestor of Yersinia pestis, which shares 95 percent of its genetic
information to produce their vaccine.13
New Regional Centers

for Biodefense Research
In September 2003, Tommy G. Thompson, secretary of
Health and Human Services, announced that $350 million
in grants was being released to establish eight Regional Cen-
ters of Excellence for Biodefense and Emerging Infectious
Diseases Research (RCE). These centers will be part of the
nation’s plan for research in biodefense. “We have moved
with unprecedented speed and determination to prepare for
a bioterror attack or any other public health crisis since the
terrorist attacks of 2001,” Thompson said. “These new grants
add to this effort and will not only better prepare us for a bio-
terrorism attack, but will also enhance our ability to deal with
any public health crisis, such as SARS and West Nile virus.”
The NIAID is providing the grants and will administer
the RCE program. “Since the terrorist attacks on American
soil in 2001, NIAID has moved rapidly to bolster basic bio-
96 plague
medical research and the development of countermeasures to

defend the United States against deliberately released agents
of bioterrorism as well as naturally occurring infectious dis-
eases,” said Anthony S. Fauci, director of NIAID. “The new
RCE program provides a coordinated and comprehensive
mechanism to support the interdisciplinary research that will
lead to new and improved therapies, vaccines, diagnostics
and other tools to protect the citizens of our country and the
world against the threat of bioterrorism and other emerging
and re-emerging diseases.”14
All of the Regional Centers for Excellence will:
• Train researchers and other personnel for biodefense

research activities.
• Create and maintain supporting resources, including

scientific equipment and trained support personnel, for
use by the RCEs and other researchers in the region.
• Emphasize research focused on development and testing of

vaccine, therapeutic, and diagnostic concepts.
• Make available core facilities to approved investigators

from academia, government, biotechnology companies,
and the pharmaceutical industry.
• Provide facilities and scientific support to first responders

in the event of a national biodefense emergency.
• Support investigator-directed research.

Each center comprises a lead institution and affiliated insti-
tutions located primarily in the same geographical region. The
eight institutions receiving an RCE grant are Duke University,
Harvard Medical School, New York State Department of Health,
University of Chicago, University of Maryland (Baltimore),
University of Texas Medical Branch (Galveston), University of
Washington, and Washington University in St. Louis. Research
to be conducted in the RCE program includes:
• Developing new approaches to blocking the action of

anthrax, botulinum, and cholera toxins.
• Developing new vaccines against anthrax, plague, tulare-

mia, smallpox, and Ebola.
• Developing new antibiotics and other therapeutic strategies.

• Studying bacterial and viral disease processes.
• Designing new advanced diagnostic approaches for
biodefense and for emerging diseases.
• Conducting immunological studies of diseases caused

by potential agents of bioterrorism.
• Developing computational and genomic approaches

to combating disease agents.
• Creating new immunization strategies and delivery

systems.
In addition to the RCE, the NIAID has funded construc-

tion of two National Biocontainment Laboratories (NBLs) and
13 Regional Biocontainment Laboratories (RBLs). The two
NBLs include the National Emerging Infectious Dieases Labo-
ratory at Boston University Medical Center and the Galveston
National Laboratory at the University of Texas Medical Branch
at Galveston. The 13 RBLs include:
• Colorado State University (Fort Collins), Regional Biocon-

tainment Laboratory
• Duke University Medical Center (Durham), Regional Bio-

containment Laboratory at Duke
• George Mason University (Manassus, VA), George Mason

University Biomedical Research Laboratory
• Tufts University, Cummings School of Veterinary

Medicine (Grafton, MA), Regional Biosafety Laboratory-
New England
98 plague
• Tulane National Primate Research Center (Covington, LA),

Regional Biocontainment Laboratory
• University of Alabama at Birmingham, School of Medi-

cine, Southeast Biosafety Laboratory Alabama
• University of Chicago, The Ricketts Laboratory
• University of Hawaii at Manoa, Pacific Regional Biocon-

tainment Laboratory
• University of Louisville, Center for Predictive Medicine
• University of Medicine and Dentistry of New Jersey

(Newark)
• New Jersey Medical School Center for Infectious Disease

Research—RBL
• University of Missouri–Columbia College of Veterinary

Medicine, University of Missouri–Columbia Regional Bio-
containment Laboratory
• University of Pittsburgh, Regional Biocontainment Labo-

ratory at the Bioscience Tower III (BST3)
• University of Tennessee Health Science Center (Memphis),

University of Tennessee Health Science Center Regional
Biocontainment Laboratory
The terrorist attacks of September 11, 2001, placed a new

emphasis on improving and increasing our national health care
facilities. Plague is just one of the deadly diseases that has come
to the attention of the public in the wake of September 11. As a
new administration takes office in Washington, scientists hope
that protection against plague continues to be a high priority.
Funding efforts ranging from basic science research to final
product development need to continue. Scientists hope that
greater awareness and additional research will help stop the
plague once and for all.
Notes
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101
Glossary
anaerobic—Not requiring oxygen.
antibiotic—A chemical produced either by a microorganism such as a bacterium

or a fungus such as a mold used to treat bacterial infections. Antibiotics are
not useful in fighting viruses. Some antibiotics are currently produced syn-
thetically either completely or in part (e.g., semisynthetic penicillins such as
ampicillin).
antibiotic resistance—Also called drug resistance; the condition when organ-
isms such as bacteria are no longer killed or inhibited by an antibiotic; the
opposite of antibiotic sensitivity.
antibody—An immune protein or immunoglobulin. These proteins are

produced by white blood cells called lymphocytes. When stimulated by
a foreign protein, chemical, or cell part, lymphocytes are converted into
protein- (antibody-) producing factories.
antigen—A molecule, group of molecules, or part of a cell that is recognized

by the host immune cells as being nonself or foreign. Antigens stimulate
production of antibodies (antibody generating).
antiphagocytic—Unable to perform phagocytosis, or able to prevent phago-

cytosis.
attenuated—Weakened.
bacillus—When the term is used with a capital “B,” it refers to a specific genus
of bacteria that have a rod-like shape; when used with a lowercase “b,” the
term refers to the a rod-like shape (a rod is longer than it is wide).
bipolar staining—Staining technique in which dye molecules concentrate at
the ends or poles of the cells, giving them the appearance of a safety pin
characteristic of Yersinia and Franciscella species.
bubo—A swelling of the lymph nodes. Adjective form is bubonic.
cholecystitis—Inflammation of the gallbladder that may be the result of infec-

tion in the gallbladder; gallstones may be present.
clinical trials—Rigorous scientific evaluation of a procedure, device, or

drug(s) used for prevention, diagnosis, or treatment of a disease. Usually
three phases (Phases I, II, III) are required for approval by the Food and
Drug Administration (FDA):
Phase I: Evaluation of clinical pharmacology, involves volunteers; testing

for safety.
102
Phase II: Performed in a small group of patients; testing for dosage and
overall desired clinical effect.
Phase III: Large, comparative study using patients to establish a clear

clinical benefit; control groups using placebos or comparisons to estab-
lished or current procedures.
coccus—Refers to shape of a bacterial cell that resembles a sphere or circle

(plural is cocci). Staphylococcus (a cluster of cocci) and streptococcus (a
chain of cocci) are common arrangements of specific groups of cocci well
known for causing diseases.
cytoskeleton—An internal protein framework inside eukaryotic cells.
endemic—Refers to frequency of disease cases in a well-defined geographic

region; frequency is low but cases are constantly present.
endotoxin—A metabolic product released from the cell walls of gram-nega-

tive bacteria when they die. Composed of lipids, polysaccharides, and
peptides, endotoxins are often toxic to the cells and may cause an inflam-
matory reaction.
enzootic reservoirs—Populations of organisms that maintain a pathogenic

organism, such as Yersinia pestis, within their population in low levels,
resulting in low mortality.
enzyme—A protein that serves as an organic catalyst, speeding up the rate of

a biochemical reaction, but not consumed or used up in that reaction. All
biochemical reactions within living systems are controlled or regulated by
enzymes.
epidemic—A dramatic increase in the number of individuals showing the

symptoms of a disease within a specified area and during a specified
time period. In the United States, statistics to determine a true epidemic
are collected and maintained by the Centers for Disease Control and
Prevention (CDC).
epizootic reservoir—Population of organisms that are highly susceptible to a

pathogen such as Yersinia pestis, with resulting high mortality.
eukaryote, eukaryotic—A type of cellular organization in which an organism

contains a nucleus and one or more cells with a nucleus and other well-
developed compartments known as organelles. These organelles consist of
membranes or are bounded by membranes.
103
facultative anaerobe—An organism that can grow and reproduce in the pres-
ence or absence of oxygen.
flagellin—A protein that is used to construct the flagella of various bacteria.
flagellum—A whip-like tail structure that helps a bacterium to move. Plural

is flagella.
free radical oxygen—Reactive by-products of metabolism; free radicals have

only single electrons in their outer energy level and remove electrons from
other molecules to complete their outer energy level; this electron stealing
sets off a chain of biochemical events in the cells, creating instability that
could destroy the cell.
GAP proteins—Proteins that activate an enzyme (GTPase) that breaks down

an energy storage molecule known as GTP (guanine triphosphate), thus
releasing energy to be used in various cellular activities.
gastroenteritis—Inflammation of the stomach and the intestines; may result in

nausea and vomiting and/or diarrhea.
genetic or gene mutation—Change in the genetic information of a cell or

virus (either DNA or RNA in some viruses); changes in genetic information
usually lead to new proteins, altered proteins or loss of proteins.
genome—The sum total of all the genetic information in a cell or virus.
genomics—The study of the totality of genetic information found in an

organism.
glycoprotein—A molecule made of simple sugars such as glucose (glyco-) and

a protein; commonly found on the outside of cell membranes and involved
in cellular recognition and rejection.
gram-negative—Refers to the designation given to bacteria that have been

stained by the Gram stain method. Gram-negative bacteria lose the color
of the first or primary stain (crystal violet) and take the color of the sec-
ond or counterstain (safranin—a red color). Thus, gram-negative cells
are red to pink in color. The organisms responsible for typhoid fever,
cholera, and bubonic plague are gram-negative.
gram-positive—Refers to the designation given to bacteria that have been

stained by the a Gram stain method. Gram-positive bacteria retain the color
of the crystal violet stain due to the composition of the cell wall and thus
are colored purple to violet.
104
inflammation—A series of responses consisting of redness, increased heat in
the area, swelling, and pain; this is followed by repair of the inflamed area
and is part of the nonspecific defenses of the body.
invasin—A protein found on the outer membrane of certain bacteria, such as

Yersinia species, which allows the bacteria to attach to the cell membrane
of human cells.
kinase—An enzyme involved in the transfer of phosphate groups on

molecules.
lipopolysaccharide (LPS)—A molecule composed of fatty acids and sugars, it

makes up a portion of the cell wall of gram-negative bacteria such as Yersinia.
lymphatic system—Includes the lymph nodes, spleen, tonsils, adenoids, and

thymus as well as scattered patches of tissue in various area of the body,
such as the intestinal mesentery. The lymphatic tissue system is part of the
body’s immune system, producing cells that help protect the body from
bacteria and other microbes.
lymph nodes—Bean-shaped organs of the lymphatic system that contain

various types of white blood cells and become swollen when infected.
lymphocytes—One of the five types of white blood cells produced by

humans; divided into B and T lymphocytes, both of which are essential
to proper immune function.
macrophage—A modified version of the monocyte, one of the five types of

white blood cells in humans. A large cell that seeks out and engulfs foreign
particles and cells through phagocytosis; literally, a “large eater.”
mutation—A change in the genetic information of a cell or virus (either DNA

or RNA in some viruses). Changes in genetic information usually lead to
new proteins, altered proteins, or loss of proteins.
nonencapsulated—Lacking a capsule or envelope.
organelles—“Miniature organs;” compartments within eukaryotic cells that

are limited or bounded by membranes; they represent the sites of various
metabolic actions and functions.
pandemic—A worldwide epidemic or widespread disease in humans; it results

when person-to-person contact occurs between individuals who have the
virus but no current immune protection against it (these types of individu-
als are sometimes called “immunologically naïve”).
105
pathogenic—Disease-causing.
plasma—The liquid portion of the blood.
plasmid—A small circle of DNA outside of the bacterial chromosome that is

capable of self-replication. These miniature chromosomes carry a limited
set of genes that can be copied and sent by means of protein tube from
one bacterium to another, increasing the genetic variability of the recipient
bacterium.
pneumonic—Refers to the lungs; a form of plague that invades the lung tis-
sue and is highly contagious.
preclinical—Studies of drugs or vaccines that are carried out in tissue or

cell cultures or animals; this phase occurs before clinical trials involving
humans.
prokaryote, prokaryotic—A type of cellular organization in which cells lack

membrane-enclosed organelles such as a nucleus; bacteria and archaea are
prokaryotic cells.
protease—An enzyme that can break down proteins.
septicemic, septicemia—Referring to large numbers of bacteria in the bacte-

rial infection of the bloodstream; sometimes known as blood poisoning.
serology—The study of the serum.
serum—The portion of the blood remaining after the blood cells, platelets, and
proteins (the formed elements) have been removed.
spirillum—A bacterium that is shaped like a spiral or curved like the letter “c.”
surveillance—A continuous and organized collection and analysis of data

regarding all aspects of a disease. This information is sent to national and
regional public health professionals, who use it to provide an up-to-date
prevention and control program.
sylvatic plague—Plague caused by organisms such as prairie dogs and

squirrels, found in natural areas such as woodlands, grasslands, or for-
ests, that carry the fleas that carry the plague organisms.
transduction—A means by which bacteria acquire fragments of DNA and

viruses transport DNA fragments from a donor cell to a recipient cell.
106
transformation—Alteration of the normal genetic information of a cell such as
a bacterium by the inclusion of additional DNA from an outside source.
urban plague—Plague caused by organisms such as rats, found in cities, that

carry the fleas that carry the plague organisms.
vaccine—A substance, organism, viral particle, or group of molecules that,

when injected or put into the body by other means, causes the immune
system to mount an immune response to that specific agent.
vectors—Organisms such as flies, fleas, and ticks that carry pathogenic organ-
isms and transmit them to other organisms.
virulence—Ability to cause disease.
107
Further Resources
Books and Articles
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Bahmanyar, M., and D.C. Cavanaugh. Plague Manual. Geneva: World Health
Organization, 1976.
Barras, Colin. “Black Death Casts a Genetic Shadow over England.” New Scien-
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for Vaccine Production in Plants.” Immunology and Cell Biology 83, no. 3
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Centers for Disease Control and Prevention. “Human Plague—Four States,
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Centers for Disease Control and Prevention. “Laboratory Test Criteria for
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Centers for Disease Control and Prevention. “Prevention of Plague. Rec-
ommendations of the Advisory Committee on Immunization Practices
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Chanteau, S., et al. “Development and Testing of a Rapid Diagnostic Test for
Bubonic and Pneumonic Plague.” The Lancet 361, no. 9353 (January 18,
2003): 211–216.
Cobbs, C.G., and D.H. Chansolme. “Plague.” American Journal of Clinical Der-
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Collinge, S.K., et al. “Testing the Generality of a Trophic-cascade Model for
Plague.” Ecohealth 2 (2005): 1–11.
Craven, R.B., and D.T. Dennis. “Plague,” in Maxcy-Rosenau-Last Public Health
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& Lange, 1998.
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Eisen, R.J., et al. “Early-phase Transmission of Yersinia pestis by Unblocked Fleas
as a Mechanism Explaining Rapidly Spreading Plague Epizootics. Proceedings
of the National Academy of the Sciences 103, no. 42 (2006): 15380–15385.
Eisen, R.J., A.P. Wilder, S.W. Bearden, J.A. Montenieri, and K.L. Gage. “Early-
phase Transmission of Yersinia pestis by Unblocked Xenopsylla cheopis
(Siphonaptera: Pulicidae) Is as Efficient as Transmission by Blocked Fleas.”
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Fleas: Secondary Infectious Feeds Prolong Efficient Transmission by Oro-
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Eisen, R.J., P.J. Reynolds, P. Ettestad, et al. “Residence-linked Human Plague
in New Mexico: A Habitat-suitability Model.” American Journal of Tropical
Medical Hygiene 77 (2007): 121–125.
Eisen, R.J., R.E. Enscore, B.J. Biggerstaff, et al. “Human Plague in the Southwestern
United States, 1957-2004: Spatial Models of Elevated Risk of Human Exposure
to Yersinia pestis.” Journal of Medical Entomology 44 (2007): 530–537.
Gage, K.L. “Yersinia,” in Cecil’s Textbook of Medicine, 23d ed. L. Goldman and
D. Ausiello, eds. Philadelphia: Elsevier, 2007.
Gage, K.L., and M.Y. Kosoy. “The Natural History of Plague: Perspectives
from More Than a Century of Research.” Annual Review of Entomology 50
(2005): 505–528.
Galimand, Marc, et al. “Minireview: Resistance of Yersinia pestis to Antimicro-
bial Agents.” Antimicrobial Agents and Chemotherapy (October 2006).
Gleba, Y., V. Klimyuk, and S. Marillonnet. “Magnifection—A New Platform
for Expressing Recombinant Vaccines in Plants.” Vaccine 23, no. 17 (2005):
2042–2048.
Guarner, J., et al. “Persistent Yersinia Pestis Antigens in Ischemic Tissues of a
Patient with Septicemic Plague.” Human Pathology 36 (2005): 850–853.
Huang, Xiao-Zhe, et al. “Current Trends in Plague Research: From Genomics
to Reed, Kurt D. “Dissecting Plague.” Clinical Medicine & Research 4, no. 3
(2006).
Inglesby, T.V., et al. “Plague as a Biological Weapon.” Journal of the American
Medical Association (May 3, 2000), http://jama.ama-assn.org/cgi/content/
full/283/17/2281 (accessed May 7, 2009).
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Josko, D. “Yersinia Pestis: Still a Plague in the 21st Century.” American Soceity
for Clinical Laboratory Science 17, no. 1 (Winter 2004): 25–29.
Lazarus, A.A., and C.F. Decker. “Plague.” Respiratory Care Clinics of North
America 10, no. 1 (March 2004): 83–98.
Lowell, J.L., et al. “Identifying Sources of Human Plague Exposure.” Journal of
Clinical Microbiology 43 (2005): 650–656.
Lowell, J.L., et al. “Phenotypic and Molecular Characterizations of Yersinia
pestis Isolates from Kazakhstan and Adjacent Regions.” Microbiology 153,
pt. 1 (2007):169–177.
Koirala, J. “Plague: Disease, Management, and Recognition of Act of Ter-
rorism.” Infectious Disease Clinics of North America 20, no. 2 (June 2006):
273–287.
Kool, J.L. “Risk of Person-to-Person Transmission of Pneumonic Plague. Clini-
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MacKenzie, Deborah. “Case Reopens on Black Death Cause.” New Scientist
(September 11, 2003), http://www.newscientist.com/article.ns?id=dn4149
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Mason, H.S., R. Chikwamba, L. Santi, et al. “Transgenic Plants for Mucosal
Vaccines,” in Mucosal Immunity 3d. ed., J. Mestecky et al. (eds.). San Diego,
Calif.: Elsevier, 2004, 1053–1060.
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5 (March 1, 2006): 614–21.
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Web Sites
Center for Infectious Disease Research and Policy
http://www.cidrap.umn.edu
Centers for Disease Control and Prevention
http://www.cdc.gov
National Institute of Allergy and Infectious Diseases
http://www3.niaid.nih.gov
National Institutes of Health
http://www.nih.gov
http://www.who.int/en
111
Index
accelerator mass spectrometry, 93 Australia, 68
Advice Against the Plague (Harvey), 52, 54 Avant Immunotherapeutics, 66
Algeria, 13
American Biotech Labs, 58 bacillus, 24, 75, 102
amino acids, 22 Bacillus anthracis, 66
anaerobic environment, 24, 102 bacteria. See also specific bacteria, e.g.:
animal feed, 70 Yersinia pestis
animals and antibiotic resistance, 70–72
plague vaccine for, 66–67 cell communication among, 90
as primary hosts, 28, 35–36, 39, 61–63 cell organization, 21
anthrax, 91 and climate change, 40
anthrax vaccine, 66 defined, 20–21
antibacterial drugs, 90–91 disabling of disease-causing mechanism
antibiotic(s) in, 87–89
and antibiotic resistance, 70 DNA sequencing, 86–87
and bacterial structure, 23 important structures of, 21–24
bioterrorism treatments, 57 motility of, 23
defined, 102 transfer of antibiotic resistance in, 73
introduction of, 51 bacterial cultures, 45
for pneumonic plague, 56 Barts and London Hospital, 18
as preferred treatment, 54 BDRD (Biological Defense Research
as prevention strategy, 60, 63 Directorate), 84
antibiotic resistance, 69–78 Beth Israel Medical Center, 10
bacterial transfer of, 73 biodefense, 54, 57, 95–98
and biological weapons, 81 “Biodefense Research Agenda for CDC
defined, 102 Category A Agents” (NIAID report),
DNA sequencing to detect, 86–87 84
evolution of resistant strains, 79–81 Biodesign Institute (Arizona State
and “hole punching” antimicrobials, University), 84
89 biofilms, 90
“master switch” research, 88 Biological Defense Research Directorate
in Yersinia pestis, 76 (BDRD), 84
antibodies biological weapon, plague as, 81–82
defined, 102 Biology of Plagues, The (Scott and
and serologic testing, 46 Duncan), 16
in serum, 25 biosafety level(s) (BSL), 49
stimulation by vaccine, 66 Biosafety Level 2 (BSL-2), 46, 47
tests for, 11 Biosafety Level 3 (BSL-3), 47, 58
and V antigens, 26 Biosafety Level 4 (BSL-4), 47, 50
Yersin’s experiments, 15 bioterrorism, 48, 57, 82–83
antigen, 66, 102 bipolar staining, 24, 102
antiphagocytic capsule, 24, 102 Black Death, 11–13, 16–18, 43
archaebacteria (archaea), 22 bloodstream, 29–31
Arizona, 19 bodily fluids, 56
ASAP-AGX-32 disinfectant, 58 Bradley, Richard, 54
aspartase, 26 Brubaker, Robert, 26
aspartic acid, 26 Brucella, 50
attenuated strains, 66, 102 BSL. See biosafety levels
112
buboes, 12, 30, 34, 43, 102. See also lymph Comprehensive Microbial Resource
nodes, swollen (CMR), 89
bubonic plague conjugation, 72, 73, 76
case study, 8–11 Connecticut, 19–20
characteristics, 41, 43 contagion, early theories of, 51–52
diagnosis of, 44–46 cultures, 46
as endemic disease, 13 cytoskeleton, 28, 103
and inflammation, 30
Buffalo Gap National Grasslands, South Daniell, Henry, 95
Dakota, 62–63 DEET (N,N-diethyl-m-toluamide), 61–62
Defense, U.S. Department of, 66
calcium, 26 Defense Threat Reduction Agency
California, 19 (DTRA), 84
capsules, 30, 74 definitive diagnosis, 45–46
carbohydrates, 22, 46 Dennis, David, 75–77
caspases, 29 deoxyribonucleic acid (DNA). See DNA
Category A bioterror agent, 82 diagnosis, 41–50, 92–93
cats, 19, 20 dipstick diagnostic test, 92, 93
causative agent, 13–16 disinfectants, 58
causes of plague, 19–31 DNA, 18, 29, 71–73
CDC. See Centers for Disease Control and DNA chips, 87
Prevention DnaK protein, 91
cell(s), organization of, 21 DNA sequencing, 82, 86–87, 89–90
cell membrane, 29, 72, 88 DNA vaccine, 84
cell walls, 21–22, 25 Dongting Lake (China), 63, 66
Centers for Disease Control and Donner Memorial State Park (California),
Prevention (CDC), 11, 48, 50, 82 19
charge, electrical, 91 doxycycline, 54, 63
China, 12–13, 63, 66 droplet transmission, 56
Chinatown, San Francisco, 64 DTRA (Defense Threat Reduction
chipmunks, 19 Agency), 84
chloramphenicol, 54, 71 Duncan, Christopher, 16
cholecystitis, 102 DynPort Vaccine Company (DVC), 94
chromosomes, 89
Cipolla, Carlo, 51 Ebers Papyrus, 12
climate change, 39–40, 85 Ebola virus, 17
Clinical Laboratory Improvement Act efflux systems, 74
(CLIA), 48 Egypt, 11, 12
clinical trials, 82, 84, 94–95, 102–103 emeralds, powdered, 52
clotting, 26 Emergency Preparedness and Response, 50
CMR (Comprehensive Microbial endemic disease, 8, 13, 103
Resource), 89 endotoxin, 25, 103
coccobacillary cells, 45 England, 12, 16
coccus, 24, 103 Enterobacteriaceae, 25
coffee, 52, 54 Environmental Protection Agency (EPA),
Colorado, 19 58
communication, among bacterial cells, 90 environmental surfaces, treatment of, 56,
competition, among microorganisms, 69 58–59
113
enzootic reservoirs, 36, 103 disabling bacterial weapons, 87
enzyme, 26, 72, 79, 103 DNA sequencing, 86–87, 89–90
EPA (Environmental Protection Agency), drug development, 93–94
58 evolution of resistant strains, 79–81
epidemics, 14, 103. See also pandemics hopes for, 86–98
epizootic reservoirs, 37, 103 nanoparticles, 91–92
Escherichia coli, 76, 78, 91 vaccine trials, 94–95
ethidium bromide, 74
eukaryotes, 21, 22, 103 gangrene, 43, 44
eukaryotic cells, 21, 103 GAP proteins, 27, 104
European plague pandemic (1300s), 12 garlic, 51, 52
extremophiles, 22 Garlimand, Marc, 77
gastroenteritis, 20, 77, 104
F1 antigen, 46, 93, 94 gene expression microarrays, 87
facultative anaerobe, 24, 104 gene sequencing, 75
Fauci, Anthony S., 85, 96 genetic exchange, 76, 77
FDA. See Food and Drug Administration, genetic information, 72
U.S. genetic (gene) mutation, 71, 104. See also
ferrets, 62–63 mutation
fibrin, 26 genome, 82, 83, 104
flagella, 23, 104 genomics, 83, 86, 104
flagellin, 23, 104 gentamicin, 54
fleas, 37 Global Outbreak and Response Network,
and antibiotic-resistant plague strain, 80
76 global warming, 63, 85
and climate change, 40 glucose, 22, 45
eradication as prevention strategy, 60, glycoprotein, 24, 104
61 gold, molten, 52
in Nile Valley, 12 gonorrhea, 72, 74
Simond’s research, 17 gram-negative bacteria
as vector of plague, 11, 12 and ASAP-AGX-32, 58
Yersinia pestis in, 28 and bubonic plague, 44–45
and Yersin’s theories on plague transmis- defined, 104
sion, 14 efflux systems in, 74
flowers, 60 Gram’s stain to identify, 22
fluorescent molecules, 86, 87 and PE, 88
folk medicine, 51 Yersinia as, 25
Food and Drug Administration, U.S. gram-positive bacteria, 22, 104
(FDA), 54, 94 Gram’s stain, 22, 41, 44
Francisella, 50 grave robbers, 52
free radical oxygen, 104 Great Pestilence. See Black Death
Frieden, Thomas, 11 groin, 44
fumigation, 61 Guiding Principles for International
future issues Outbreak Alert and Response (WHO
antibacterial drugs, 90–91 document), 80
cell communication, 90
concerns for, 79–85 Hantavirus, 93
diagnostic tests, 92–93 Harvey, Gideon, 52, 54
114
Heska Corporation, 66 Klabunde, Kenneth K., 91
history of plague, 8–18 Kramer, Vicki, 19
early means of prevention, 60
early treatments, 51–54 laboratory diagnosis techniques, 44–48,
use as biological weapon, 81–82 50
“hole punching” antimicrobials, 88–89 Laboratory Response Network (LRN), 47,
Hong Kong epidemic (1894), 14 48, 50, 59
horizontal transfer, 76 Lawrence Livermore Laboratory, 93
horses, 15 leeches, 52
host animal. See animals, as primary hosts lesions, 44, 56
host cell, invasion by Yersinia pestis, 26–29 lipopolysaccharide (LPS), 25, 105
Huang, Xuefei, 91 live oral vaccine, 95
Hughes, James, 75–77 liver, 30, 44
Liverpool University School of Biological
Ichor Medical Systems, 84 Sciences, 16
Icon Genetics (Halle, Germany), 84 livestock, 70, 77–78
immune system London, England, 53
evasion by Yersinia, 79 LPS. See lipopolysaccharide
and flagellin, 23 LRN. See Laboratory Response Network
and inflammation, 30 lucky charms, 60
macrophages as part of, 28–30 lungs, 30, 31, 42
and O antigen, 25 lymphatic system, 30, 105
and peptidoglycan, 22 lymph nodes, 30, 42, 105
immunofluorescent staining of capsule, lymph nodes, swollen
44, 45 and Black Death, 12
inactivated proteins, 15 and bubonic plague, 16, 41, 43, 44
incubation period, 44 and immune system, 30
India, 13, 15–16 and pneumonic plague, 31
Indonesia, 13 lymphocytes, 105
inflammation, 20, 30, 105
inoculation, 15. See also vaccination macrophage, 28–30, 105
insecticides, 61 Madagascar, 76
insect repellents, 61 magnesium oxide, 91
insects, peptides in, 90–91 magnetic glyco-nanoparticle (MGNP),
intestinal bacteria, 70 91
invasin, 26, 105 “Magnetic Glyco-Nanoparticles: A Unique
in vitro dosage, 58 Tool for Rapid Pathogen Detection,
ions, 93 Decontamination, and Strain
iron, 24 Differentiation” (Huang et al), 91
isolation, 55, 56. See also quarantine Mahan, Michael, 88
mammals, 37, 39
John, George, 92 mannitol, 46
Marker, Lucinda, 8–11
Kaffa, Ukraine, 81 marmots, 20
Kansas State University, 91 “master switch,” 87, 88
Kazakhstan, 39 MDR (multiple drug-resistant) pathogens,
kinase, 27, 105 74
kingdoms (categories), 20–21 membrane, 29, 72
115
MGNP (magnetic glyco-nanoparticle), 91 Old Dominion University (Norfolk,
miasma, 51 Virginia), 74
miasmatic paradigm, 51–52 online diagnosis, 50
mice, 19, 36 oral vaccine, 66, 95
microarrays, 87 organelles, 21, 26–27, 105
microbial genomics, 83 oriental rat flea, 37
Microtus, 36 outer membrane, 25
Middle Ages, 52, 53 Oxford University, 18
midgut, 76, 79
Ministry of Health (China), 63 Panagiotakopulu, Eva, 12
mitochondria, 29 pandemics, 11–13, 105
Moeller, Keith, 58 parasites, 70
monkeys, 19 passive hemagglutination test, 45
monoclonal antibodies, 94 Pasteurella pestis, 24
Morens, David, 85 Pasteur Institute, 14, 16, 92–93, 95
“Multidrug Resistance in Yersinia pestis pathogenic species, 20, 106
Mediated by a Transferable Plasmid” PCR-based plasmid typing, 86
(Garlimand et al), 77 PE (phosphoethanolamine), 88–89
multiple drug-resistant (MDR) pathogens, penicillinase, 74
74, 77–78 penicillinase-producing Neisseria gonor-
mutation, 26, 71, 89, 105 rhea (PPNG), 74
peptides, 90–91
N,N-diethyl-m-toluamide (DEET), 61–62 peptidoglycan, 22, 23, 25
nanoparticles, 91–92 perfumes, 60
National Biocontainment Laboratories permethrin, 61
(NBLs), 97 Peromyscus, 36
National Institute of Allergy and Infectious pesthouses, 60
Diseases (NIAID), 75, 83–85, 93, 95–96 phagocytic white blood cells, 28
national LRN laboratories, 47, 59 phagocytosis, 79–80
National Medical Society, 50 pheromones, 90
Natural Bridges National Monument phosphoethanolamine (PE), 88–89
(Utah), 19 phospholipase D (PLD), 79
NBLs (National Biocontainment phospholipids, 25
Laboratories), 97 pilus, 72
New Mexico, 8, 11, 13, 20, 32–35 plasma, 15, 25, 106
New York City, 8–11 plasma membrane, 29
New York City Department of Health, 10 plasmids, 24, 71, 72, 76, 106
NIAID. See National Institute of Allergy plasminogen activator, 26
and Infectious Diseases Plasmodium, 75
Nile rat, 12 PLD (phospholipase D), 79
Nile Valley, Egypt, 12 pneumonia, 41
nonencapsulated bacteria, 24, 105 pneumonic plague, 20, 43, 56, 93, 106
North Africa, 11 polymorphonucleated neutrophils
Norway rat, 36 (PMNs), 28, 30
nucleus, 21 PPNG (penicillinase-producing Neisseria
gonorrhea), 74
O antigen, 25 prairie dogs, 62–63
odor, 60 preclinical (term), 106
116
presumptive diagnosis, 44–45 septicemia, 106
prevention, 60–68 septicemic (term), 106
priests, 52 septicemic plague, 31, 44
Primas, Ronald, 9, 10 serologic testing, 45, 46
prokaryotic cells, 21, 106 serology, 46, 106
protease, 27, 106 serum, 15, 16, 25, 106
proteins, 15, 22 17/95 biotype orientalis, 76
proventricular plague mass, 37 Seville, Spain, 52
pseudogenes, 89 sheep blood agar, 46
Pyrrhocoris apterus, 91 side-chains, 25
silver, 51
quarantine, 16, 52, 60, 64 silver nanoparticles, 92
quorum sensing, 90 Simond, Paul-Louis, 17
skin lesions, 44, 56
rats, 14, 17, 38, 61, 63, 65 smoke, 60
RBLs (Regional Biocontainment Society of General Microbiology, 18
Laboratories), 97–98 Soviet Union, 81
RCE (Regional Centers of Excellence for Spain, 52
Biodefense and Emerging Infectious spirillum, 24, 106
Diseases Research), 95–98 spleen, 30, 44
recombinant vaccine, 94 sputum, 43
reemerging disease, 77, 84–85 squirrels, 19, 34, 36
reference LRN laboratories, 47, 48, 50, 59 Stebbins, C. Erec, 81
Regional Biocontainment Laboratories Straley, Susan, 27, 30, 31
(RBLs), 97–98 streptomycin, 54, 55
Regional Centers of Excellence for Structural Biology Laboratory (Argonne
Biodefense and Emerging Infectious National Laboratories), 90
Diseases Research (RCE), 95–98 “Study of Ancient and Modern Plagues
repellents, 61 Finds Common Features” (NIAID
reproduction of microorganisms, 71 report), 85
rF1V vaccine, 94 sulfonamides, 63
Rockefeller University (New York), 79 Suntsov, Victor, 20
rock squirrels, 34, 36 surgical masks, 56
rodents, 37, 38, 60, 61. See also rats surveillance, 76–77, 106
rosemary, 51, 52 sylvatic plague, 38, 106
symptoms, 16
Salmonella, 78, 88
Sanderson, Steven, 85 Tatars, 81
San Francisco plague cases (1900-1909), temperature, 28, 40
64–65 tetracycline, 54, 63
sanitation, 52 Thompson, Tommy G., 95
Santa Fe County, New Mexico, 11, 20 thyme, 51, 52
Scott, Susan, 16 Titball, Rick, 82
sea trade, 12 tobacco leaves, 84
select agent, 46 toxins, 15
sentinel LRN laboratories, 47, 48 transduction, 72, 73, 106
September 11, 2001, terrorism attacks, 8, transformation, 71–73, 107
9, 56, 98 transmission, 17, 79
117
TraR protein, 90 Wildlife Conservation Society, 84–85
treatment, 51–59 Wind Cave National Park, 63
tree squirrels, 35 Wistar Institute, 90
trimethoprim-sulfamethoxazole, 54 Wong, Gerard, 88
Tull, John, 8–11 Wood, James, 17
type III secretion system, 26–27 Working Group on Civilian Biodefense,
54, 57, 82
ulcerations, 12 World Health Organization (WHO), 80,
United States 82–83
cold war biological weapons programs, World War II, 81
81 Wright’s stain, 23
plague in, 10m, 11, 13 Wyoming, 19–20
University of Central Florida, 95
University of Illinois, 88 Xenopsylla cheopis, 37
University of Massachusetts, 88 X-rays, 41
University of Rochester Medical Center, 86 Xu, X. Nancy, 74
urban plague, 38, 107
U.S. Army Medical Research Institute for Yersin, Alexander, 13–16, 24
Infectious Disease, 84 Yersinia spp. , 20
Utah, 19 Yersinia enterocolitica, 20
Yersinia pestis, 23
vaccination, 60, 63, 66–68 and alternate Black Death theories, 18
vaccines antibiotic-resistant strain, 69, 76
and bacterial structure, 23 and ASAP-AGX-32, 58
clinical trials, 94–95 as biological weapon, 81
defined, 107 as cause of plague, 8
and microbe genome, 82 characteristics of, 24
NIAID research, 84 discovery/naming of, 14
Yersin’s experiments, 15 DNA sequencing of, 89–90
V (virulence) antigens, 25, 26, 94 evolution of resistant strains, 79–81
vectors, 11, 107 in fleas, 28
Vietnam War, 66 invasion of host cell by, 26–29
viral infections, 70 invasion of host’s bloodstream, 29–31
Virtue and Use of Coffee with Regard to the “master switch” research, 88
Plague and Other Infectious Distempers and MDR genetic information, 77
(Bradley), 54 and pneumonic plague, 56
virulence, 107 primary hosts for, 35–36
virulence factors, 24–26, 81 and reference laboratories, 50
viruses, 72, 73 vaccine against, 66
viability on external surfaces, 59
W antigens, 25 virulence factors, 24–26
Wayson stain, 41, 44 Yersinia pseudotuberculosis, 20, 89
weapon, plague as, 81–82 Yops toxins, 27–28
western United States, 13 York, Eric, 19
white blood cells, 25
WHO. See World Health Organization Zhang, Rong-guang, 90
118
About the Author
Dr. Donald Emmeluth spent most of his teaching career in upstate New
York. In 1999, Dr. Emmeluth retired from the State University of New York
system and moved to Savannah, Georgia. He became a member of the Biol-
ogy Department of Armstrong Atlantic State University in Savannah, where
he teaches a number of courses.
Dr. Emmeluth has published several journal articles and is the co-author
of a high school biology textbook. His most recent article appeared in the
February 2002 issue of The American Biology Teacher. He has also authored
three other books in the Deadly Diseases and Epidemics series: Typhoid Fever,
Plague, and Botulism.
Dr. Emmeluth has served as President of the National Association of Biology
Teachers. During his career, Dr. Emmeluth has received a number of honors
and awards including the Chancellor’s Award for Excellence in Teaching from
the State University of New York system and the Two-Year College Biology
Teaching Award from NABT. In 2003, Dr. Emmeluth was awarded NABT’s
Honorary Membership Award for outstanding contributions to Biology and
Life Science Education. This award is the association’s highest honor.
About the Consulting Editor

Hilary Babcock, M.D., M.P.H., is an assistant professor of medicine at
Washington University School of Medicine at Washington University School
of Medicine and the Medical Director of Occupational Health for Barnes-Jew-
ish Hospital and St. Louis Children’s Hospital. She received her undergradu-
ate degree from Brown University and her M.D. from the University of Texas
Southwestern Medical Center at Dallas. After completing her residency, chief
residency, and Infectious Disease fellowship at Barnes-Jewish Hospital, she
joined the faculty of the Infectious Disease division. She completed an M.P.H.
in Public Health from St. Louis University School of Public Health in 2006.
She has lectured, taught, and written extensively about infectious diseases,
their treatment, and their prevention. She is a member of numerous medical
associations and is board certified in infectious disease. She lives in St. Louis,
Missouri.
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Plague

Donald Emmeluth, Ed.D.

Copyright © 2010 by Infobase Publishing, Inc.

Library of Congress Cataloging-in-Publication Data

Series design by Terry Mallon

Printed in the United States of America

This book is printed on acid-free paper.

2. Causes of the Plague 19

3. Cats, Rats, Prairie Dogs, and Squirrels 32

7. The Problems of Antibiotic Resistance 69

8. Concerns for the Future 79

9. Hopes for the Future 86

Further Resources 108

About the Author 120

About the Consulting Editor 120

the effectiveness of vaccines better than the successful eradication of

sized city, it lacked the character and excitement of New

Number of Plague Cases by County, 1970–2002

Figure 1.1 Although many people think of plague as something from

Dr. Primas referred the couple to Beth Israel Medical

that involved checking their blood for the presence of certain

The Present-day Plague

The Black Death

bacteria. Dr. Eva Panagiotakopulu and her colleagues found

the plague organism moved with them. It continued to spread

caused by a bacterium that ultimately was named after him,

Figure 1.2 Alexandre Yersin, who identified the causative agent of

In an attempt to produce a vaccine to protect people

In 1897, Alexander Yersin left the Pasteur Institute and

Black Death Was Not

Dr. Paul-Louis Simond picked up plague research where Alexan-

an exhaustive review of described symptoms and primitive

The French and English

Bridger-Teton National Forest, and other sites in Wyoming.

Origin of the Plague Organism

What Are Bacteria?

Plantae (plants), Animalia (animals), Fungi, Protista, and

Important Bacterial Structures

Archaea — A Third Form of Life

a molecule called peptidoglycan that contains amino acids,

Figure 2.1 One way to test for the presence of the

It is also important to know that bacteria can move on their

Characteristics of Yersinia pestis

Factors Involved in Yersinia’s Virulence

The bubonic plague organism, like other members of its

that Yersinia pestis is so virulent is its ability to survive and

Needling the Host Cell

membrane and anchored in the inner and outer membranes”

These proteins collectively overcome the host’s natural defenses

The Life of the Flea

Figure 2.3 Some pathogens, such as the plague-causing bacterium

diFFereNT maNiFesTaTioNs oF The plague

the danger. Ironically, the bacteria find a safe place to live

Because the inhaled bacteria have already adapted to the

First Stop—The Hospital?

“bubonic plague!” shouted Jim.

As Zachary and Jim got to the hospital room, Al greeted

What Types of Animals Carry the Plague

Figure 3.1 Tree squirrels are a known carrier of Yersinia pestis.

between humans and the infected fleas of infected rodents. In

Different Levels of Infection

resistance to the plague organism varies from one geographi-

sylvaTiC aNd urBaN plague

When plague organisms are found mainly in the fleas of rodents,