PATHOGENESIS

&
HOST DEFENSES
PATHOGENESIS
I. INTRODUCTION
II. TYPES OF BACTERIAL INFECTIONS
III. DETERMINANTS OF BACTERIAL
PATHOGENESIS
IV. TYPICAL STAGES OF AN INFECTIOUS
DISEASES
I. INTRODUCTION:
Pathogens:
– A microorganism is a pathogen if it is capable of causing
disease.
– Some organisms are frequently pathogens, whereas
others cause disease rarely.
Opportunistic pathogens
– are those that rarely cause disease in immunocompetent
people but can cause serious infections in
immunocompromised patients.
– They are frequently members of the body's normal flora.
– The origin of the term 'opportunistic" refers to the ability
of the organism to take the opportunity offered by
reduced host defenses to cause disease.
Virulence:
• is a quantitative measure of pathogenicity and is
measured by the number of organisms required to
cause disease.
• The 50% lethal dose (LD 50):
– is the number of organisms needed to kill half the hosts.
• The 50% infectious dose (ID50):
– is the number needed to cause infection in half the hosts.
– E.g. ID required to cause dease:
• Shegella: 100 organisms.
• Salmonella: 100,000 organisms.
• The infectious dose of bacteria depends
primarily on the number of the organism and
their "virulence factors, " for example:
• Pili - adhere mucous membranes.
• Exotoxins
• Endotoxins,
• Capsule - to protect from phagocytosis.
• Surviving various non-specific host defenses
(such as acid in the stomach).
• There are two uses of the word parasite. Within the
context of this chapter, the term refers to the parasitic
relationship of the bacteria to the host cells (i.e., the
presence of the bacteria is detrimental to the host cells).
Bacteria that are human pathogens can be thought of,
therefore, as parasites.
• Some bacterial pathogens are obligate intracellular
parasites (e.g., Chlamydia and Rickettsia), because
they can grow only within host cells.
• Many bacteria are facultative parasites because they can
grow within cells, outside cells, or on bacteriologic
media.
• The other use of the term parasite refers to the protozoa
and the helminths, which are discussed in Parasitology
field.
• ) WHY DO PEOPLE GET INFECTIOUS DISEASES?
• People get infectious diseases when microorganisms
overpower our host defenses (i.e., when the balance
between the organism and the host shifts in favor of the
• organism).
• The organism or its products are then present in sufficient
amount to induce various symptoms, such as fever and
inflammation, which we interpret as those of an infectious
disease..
• From the organism’s perspective, the two critical
determinants in overpowering the host are the number of
organisms to which the host, or person, is exposed and
the virulence of these organisms. Clearly, the greater the
number of organisms, the greater is the likelihood of
infection.
• From the host’s perspective, the two main arms of our
host defenses are innate immunity and acquired
immunity, the latter of which includes both antibody
mediated and cell-mediated immunity.
• A reduction in the functioning of any component of our
host defenses shifts the balance in favor of the organism
and increases the chance that an infectious disease will
occur.
• Some important causes of a reduction in our host
defenses include genetic immunodeficiencies such as
agammaglobulinemia and acquired immunodeficiencies
such as acquired immunodeficiency syndrome (AIDS),
drug-induced immunosuppression in patients with organ
transplants, cancer patients who are receiving
chemotherapy and steroids. .
BACTERIAL STRUCTURE
 CELL WALL STRUCTURES
GRAM POSITIVE AND GRAM NEGATIVE
BACTERIA
II. TYPES OF BACTERIAL INFECTIONS

CAUSING THE DISEASE:

• Bacteria cause disease by 2 major mechanisms:
– Toxin production.
– Invasiveness.
• Toxins fall into 2 general categories (table)
– Exotoxins.
– Endotoxins.
• Exotoxins are polypeptides released by the cell-
whereas endotoxins are lipopolysaccharides. which
form an integral part of the cell wall.
• Endotoxins occur only in Gram-negative rods and
cocci: are not actively released from the cell
• Endotoxins cause fever, shock, and other generalized
symptoms.
• Both exotoxins and endotoxins by themselves can
cause symptoms; the presence of the bacteria in the
host is not required.
• Invasive bacteria, on the other hand grow to large
numbers locally and cause symptoms in that area by
producing a variety of enzymes that damage
adjacent host cells.
• enzymes that damage adjacent host cells.
• Many but not all infections are communicable, i.e.:are
spread from host to host.
• For example:
• Tuberculosis is communicable, as it is spread from
person to person via airborne droplets produced by
coughing:
• Botulism is not communicable as the exotoxin produced
by the organism in the contaminated food affects only
those eating that food.
• If a disease is highly communicable, the term
"contagious " is applied.
• Epidemic:
– An infection is epidemic if it occurs much more frequently
than usual.
• Pandemic:
– It is pandemic if it has a worldwide distribution.
• Endemic:
– An endemic infection is constantly present at a low
level in a specific population.
• In addition to infections that result in overt symptoms,
many are inapparent or subclinical and can he detected
only by demonstrating a rise in antibody titer or
isolating the organism.
• Chronic carrier state:
– Certain other infections lead to a chronic carrier
state, in which the organisms continue to grow
with or without producing symptoms in the host
(eg.Typhoid Fever).
• Colonization
– refers to the presence of a new organism that is
neither a member of the normal flora nor the
cause of symptoms.
STAGES OF BACTERIAL PATHOGENESIS
• Most bacterial infections are acquired from an external
source. However, some bacterial infections are caused by
members of the normal flora and, as such, are not
transmitted directly prior to the onset of infection.
• A generalized sequence of the stages of infection is as
follows:
A generalized sequence of the stages of infection is as
follows:
1. Transmission from an external source into the portal of
entry.
2. Evasion of primary host defenses such as skin or stomach
acid.
3. Adherence to mucous membranes, usually by bacterial
pili.
4. Colonization by growth of the bacteria at the site of
adherence.
5. Disease symptoms caused by toxin production or invasion
accompanied by inflammation.
6. Host responses, both nonspecific and specific (immunity),
during steps 3, 4, and 5.
7. Progression or resolution of the disease
III. DETERMINANTS OF BACTERIAL PATHOGENESIS

The determinants of bacterial pathogenesis are:

1. Transmission
2. Adherence to cell surfaces
3. Invasiveness
4. Toxins
1.TRANSMISSION
• Although some infections are caused by members of the
normal flora.
• Most are acquired by transmission from external
sources.
• Pathogens exit the infected patient most frequently from
the respiratory and gastrointestinal tracts: thus,
transmission to the new host usually occurs via airborne
respiratory droplets or fecal contamination of food and
water.
• Organisms can also be transmitted by sexual contact,
urine, skin contact, blood transfusions. contaminated
needles, or biting insects.
• The 4 important portals of entry (seeTable) are. :
– respiratory tract
– gastrointestinal tract.
– genital tract. and
– skin
• Animals can also be an important source of organisms
that infect humans.
• They can be either the source (reservoir).
• Can be the mode of transmission (vector) of certain
organisms.
• Diseases for which animals are the reservoirs are called
zoonoses.
• Bacteria, viruses, and other microbes can also be
transmitted from mother to offspring, a process called
vertical transmission. The three modes by which
organisms are transmitted vertically are across the
placenta, within the birth canal during birth, and via breast
milk. Table 2 describes some medically important organisms
that are transmitted vertically.
• Horizontal transmission, by contrast, is person-to-person
transmission that is not from mother to offspring.)
Important Modes of Transmission
Table 2:Vertical Transmission of Some Important
Pathogens
TABLE 3 : Portals of Entry of Some Common Pathogens
TABLE 4: Transmission of Important Waterborne
Diseases
TABLE 5: Bacterial Diseases Transmitted by Foods
TABLE 6: Bacterial Diseases Transmitted by Insects
TABLE 7: Zoonotic Diseases Caused by Bacteria
2. ADHERENCE TO CELL SURFACES
• Certain bacteria have specialized structures or contain
substances that allow them to adhere to the surface of
human cells, thereby enhancing their ability to cause
disease.
• These adherence mechanisms are essential for
organisms that attach to mucous membranes.
• Mutants that lack these mechanisms are often non-
pathogenic.
• For example, the pili of Neisseria gonorrhoeae and
Escherichia coil .
3. INVASIVENESS

• One of the 2 main mechanisms by which bacteria cause

disease is invasion of tissue followed by inflammation.

• Several enzymes secreted by invasive bacteria play a

role in pathogenesis. Among the most important are:

A. Enzymes
i. Collagenase (degrade collagen) & hyaluronidase (degrade
hyaluronic acid).
– These enzymes allow the bacteria to spread through
subcutaneous tissue (e.g. cellulitis caused by Streptococcus
pyogenes).
ii. Coagulase
– which is produced by Staphylococcus aureus and accelerates
the formation of a fibrin clot from its precursor, fibrinogen.
– This clot may protect the bacteria from phagocytosis by walling
off the infected area and by coating the organisms with a layer
of fibrin.
iii. Immunoglobulin A (IgA) protease
– It degrades IgA, allowing the organism to adhere to mucous
membranes (produced by N gonorrhoeae, Haemophilus
influenzae, and Streptococcus pneumoniae).
iv. leukocidins,
– It can destroy both neutrophilic leukocytes and macrophages.
B. others (non-enzyme) factors:
• In addition to these enzymes, several factors contribute to
invasiveness by limiting the ability of the host defense
mechanisms, especially phagocytosis, to operate effectively.
i. Capsule
– The most important of these factors is the capsule of several
important pathogens (S pneumoniae and Neisseria
meningitidis).
– The polysaccharide capsule prevents the phagocyte from
adhering to the bacteria.
– The vaccines against S pneumoniae, H influenzae. And N
meningitidis contain capsular polysaccharides.
ii. second group of anti-phagocytic factors are the cell wall
proteins of the Gram-positive cocci (M protein of the
group A Streptococcus and protein A of the
Staphylococci).
– Virulence factors are summarized in the Table (2).below .
TABLE 8 Surface Virulence Factors Important for
Bacterial Pathogenesis
4. TOXIN PRODUCTION
• A comparison of the main feutures of
exotoxins and endotoxin is shown in table
below
 Table 3. Main features of exotoxins and endotoxins

Property Comparison of Properties

Exotoxin Endotoxin
Mode of action Various modes Induces TNF and IL

Antigenicity Induces high-titer Poorly antigenic

Ab called antitoxins
Vaccines Toxoids used as No toxoids formed
vaccines and no vaccine available
Heat stability Destroyed rapidly at Stable at 100 °C for 1
60°C (except Staph hour
enterotoxin)
Typical diseases Tetanus, botulism, Meningococcemia,
diphtheria Sepsis by G N rods
 Table 3. Main features of exotoxins and endotoxins (cont.).

Property Comparison of Properties

Exotoxin Endotoxin
Source Certain species of Cell wall of most GN
some GP & GN bacteria
Secreted from cell Yes No
Chemistry Polypeptide Lipopolysaccharide
Location of genes Plasmid or Bacterial
bacteriophage chromosome

Toxicity High (fatal dose on Low (fatal dose on

the order of 1μg) the order of hundreds
of μg)
Clinical effects. Various effects Fever, shock
A. Exotoxins
• are produced by:
– several gram-positive and Gram-negative bacteria in contrast to endotoxin
which are present only in Gram-negative bacteria.
• Exotoxins are characterized by:
– They are secreted by the bacteria, whereas endotoxin is a component of
the cell wall.
– They are polypeptides that their genes are frequently located on plasmids
or lysogenic bacterial viruses (bacteriophages).
– Exotoxins are among the most toxic substances known.
– For example, the fatal dose of tetanus toxin for a human is estimated to be
less than I pg.
– Because some purified exotoxins can reproduce all aspects of the disease.
• Exotoxin polypeptides are good antigens and
induce the synthesis of protective antibodies
called antitoxins, some of which are useful in
prevention or treatment of diseases such as
botulism and tetanus.
• When treated with formaldehyde (or acid or
heat), the exotoxin polypeptides are converted
into toxoids, which are used in protective vaccines
because they retain their antigenicity but have
lost their toxicity.
• The mechanisms of action of the important
exotoxins produced by toxigenic bacteria differ
significantly as described below and summarized
in Table 4.
The important exotoxins produced by toxigenic bacteria (Table 4).
1. Diphtheria toxin:
– produced by Corynebacterium diphtheriae.
– Inhibits protein synthesis by ADP ribosylationof elongation
factor 2 (EF-2).
2. Tetanus toxin ((tetanospasmin):
– Produced by Clostridium tetani.
– Is a neurotoxin that prevents release of the inhibitory
neurotransmitter glycine.
– It causes muscle spasms.
3. Botulinum toxin:
– Produced by Clostridium botulinum.
– Is a neurotoxin that blocks the release of acetylcholine at the
synapse, producing paralysis.
4. The heat-labile enterotoxin:
– Produced by E coil.
– causes diarrhea by stimulating adenylate cyclase activity in cells in
the small intestine.
5. Bordetella pertussus toxins:
– causes of whooping cough.
– Enhances adenylate cyclase activity.
6. Bacillus anthracis exotoxins:
– Are 3 exotoxin produced by the agent of anthrax: Edema factor,
protective antigen, and lethal factor.
7. Toxic shock syndrome toxin (TSST):
– Is produced by certain strains of Staphylococcus aureus.
8. Multiple toxins
– Are produced by Clostridium perfringens and other species of
clostridia that cause gas gangrene.
9. Erythrogenic toxin
– produced by Streptococcus pyogenes causes the rash characteristic
of scarlet fever.
B. Endotoxins
– Endotoxins are integral parts of the cell walls of both gram-negative
rods and cocci, in contrast to exotoxins which are released from the
cell. (see Table ).

The biologic effects of endotoxin (Table ) include:

i. Fever due to the release by macrophages of' endogenous pyrogen
(interleukin- I), which acts on the hypothalamic temperature-
regulatory center:
ii. Hypotension, shock, and impaired perfusion of essential organs
owing to bradykinin-induced vasodilatation, increased vascular
permeability, and decreased peripheral resistance.
iii. Disseminated intravascular coagulation due to activation of the
coagulation system through Hageman factor (factor XII) resulting
in thrombosis and tissue ischemia.
iv. Activation of the alternative pathway of the complement cascade,
resulting in inflammation and tissue damage.
v. Activation of macrophages, increasing their phagocytic ability, and
activation of many clones of B lymphocytes, increasing antibody
production.
 EFFECTS OF ENDOTOXIN
Clinical Findings Mediator or Mechanism

Fever interleukin-1

Hypotension (shock) Bradykinin, nitric oxide

Inflammation Alternative pathway of

complement (C3a, C5a)

Coagulation (disseminated intravascular Activation of Hageman factor

coagulation - DIC)
FIGURE : Mode of action of endotoxin. Endotoxin is the
most important
IV. TYPICAL STAGES OF AN INFECTIOUS DISEASES
A typical acute infectious disease has 4 stages:
1. The incubation period:
• Is the time between the acquisition of the organism (or toxin) and
the beginning of symptoms (this time varies from hours to days
to weeks depending on the organism).
2. The prodrome period:
• During which non-specific symptoms such as fever, malaise and
loss of appetite occur.
3. The specific-illness period:
• During which the overt characteristic signs and symptoms of the
disease occur.
4. recovery period:
• During which the illness abates and the patient returns to the
healthy state.
"Koch's postulates"
• which are criteria that proposed by Robert Koch.
• These criteria must be satisfied to confirm the causal
role of an organism.
• These criteria are:
1. The organism must be isolated from every patient with the
disease.
2. The organism must be isolated free from all other organisms
and grown in pure culture in vitro.
3. The pure organism must cause the disease in a healthy,
susceptible animal.
4. The organism must be recovered from the inoculated
animal.
Host Defenses
Host defences are composed of 2 systems:
1. Non-specifi immunity.
– which protect against microorganisms in general.
2. specific immunity.
– which protects against a particular microorganisms.
IMMUNITY
1. Non-specific immunity.
• These mechanisms are very diverse: they include,
for example:
– Physical barriers
– Chemical substances
– Phagocytes.
• Most of the non-specific defense mechanisms are
innate, rather than acquired, and are present all
the time. Most are so obvious and effective that we
don't notice them.
A. Physical mechanisms of non-specific immunity
i. Physical barriers to invasion
– Skin and mucous membranes and other integuments
of the body prevent organisms from entering and
spreading.
– Some anatomical sites, e.g. the meninges.
– Tears, urine or blood (in a wound) all help to wash
foreign matter away from where it may cause
infection.
– The motion of cilia in the respiratory tract keeps the
layer of mucus moving upwards at a rate of about 2
cm/hr, along with the airborne bacteria that stick to it.
– Reflexes like coughing and sneezing help to
expel foreign matter from the respiratory tract.
– Continual desquamation of the skin (shedding of
superficial layers) gets rid of potential skin
pathogens.
– Air inhaled through the nostrils is given a
swirling motion because of the conchoidal or
helical shape of the nasal vestibule.
B. Chemical mechanisms of non-specific immunity
• Acid in stomach.
– The contents of the stomach contain hydrochloric acid at
a concentration of about 0.1M. Most bacterial cells
exposed to this will die in about 1 minute.
– Some drugs, summer weather, and antacids will raise the
pH and make people more susceptible to gastrointestinal
infection.
• Salt and Fatty acids in skin.
– The salt is provided by the sweat glands; some of the
fatty acids are made in the sebaceous glands and some
are metabolic by-products of normal bacterial flora.
• Lysozyme.
– An enzyme that occurs in tears, nasal and
gastrointestinal secretions, saliva.
– Its site of action on the bacterial cell wall.
– It can kill some bacterial species by itself, and helps to
kill and digest many others.
• Complement
• Oxygen
– In healthy tissues prevents the growth of strict
anaerobes.
• Acute phase proteins
– Are produced during many inflammatory diseases.
• Temperature
C. Cellular mechanisms of non-specific immunity
• These are mediated by the following cells,
• macrophages
• polymorphs
− neutrophils
− eosinophils
− basophils
• natural killer cells
2. Mechanisms of specific immunity
• Antibody
– Produced by lymphocytes B.
• Cell-Mediated Immunity (CMI)
– Involve lymphocytes T.
There are 2 types of immunity directed against
specific organisms:
• Natural immunity:
– Which occurs In the absence of exposure to the
organisms.

• Acquired immunity
– which results either from exposure of the organism
(active immunity) or
– from receipt of preformed antibody made in
another host (Passive immunity).