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Module VIII
BACTERIAL VIRULENCE

Infection is the entry and invasion of a susceptible host by microorganisms

which multiply in the host tissues. Bacteria can cause a multitude of different
infections, ranging in severity from inapparent to fulminating. Virulence is the
measure of the pathogenicity of an organism. The degree of virulence is related
directly to the ability of the organism to cause a disease despite host resistance
mechanisms. Virulence is affected by numerous variables such as the number
of infecting bacteria, route of entry into the body, specific and non-specific host
defense mechanisms and the virulence factors of the bacterium.
Virulence can be measured experimentally by determining the number of
bacteria required to cause animal death, illness or lesions in a defined period
after the bacteria are administered by a designated route. Pathogenesis refers
both to the mechanism of infection and to the mechanism by which a disease
develops. Ability of a bacterium to cause infection results from a disturbance in
the balance between bacterial virulence and host resistance.
A study on bacterial virulence factors lays the ground in understanding
the role of these molecules in bacterial infection. This also provides a preliminary
knowledge on the capacity of bacterial pathogens to outmaneuver host defense
mechanisms in their attempt to proliferate in the host and initiate an infection
or a disease.

Objectives:
On successful completion of the module, students will be able to:
1. Identify 3 mechanisms which evoke bacterial virulence.
2. Describe the virulence of capsule-derived molecules.
3. Discuss the virulence of bacterial endotoxins paying special attention to the
action of its Lipid A.

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The capacity of a bacterium to cause disease reflects its pathogenicity.

Bacteria can be organized into three major groups based on virulence and these
include primary, opportunistic and non-pathogenic forms. When a bacterium is
isolated from a sick animal, primary pathogens are considered as probable
agents of infection (e.g. when the cause of the disease is identified by laboratory
isolation of the organism from host tissues). Opportunistic pathogens comprised
of those bacteria isolated from animals with compromised host defense

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mechanisms may be considered as agents of the infection. Non-pathogenic

bacteria are those that are rarely or never caused a disease. The non-pathogenic
nature of bacteria may reportedly change because of the adaptability of bacteria
to mount resistance mechanisms.

Genetic and molecular basis for bacterial virulence

Bacterial virulence factors may be encoded in the plasmid, transposon or
the bacterial chromosome. The capacity of some bacteria (Shigella spp.) to invade
cells is a property reportedly encoded in part on a 140-mega-dalton plasmid.
Similarly, the heat-labile enterotoxin (LTI) of E. coli is reportedly plasmid encoded
while the heat-labile toxin (LTII) is encoded on the chromosome. Other virulence
factors are reportedly acquired by bacteria following infection by a particular
bacteriophage, which integrates its genome into the bacterial chromosome by
the process of lysogeny. Other virulence factors (cholera
toxin, Salmonella enterotoxin and Yersinia invasion factors) are reportedly
encoded in the bacterial chromosome.
The transfer of genes for antibiotic resistance among bacteria is a
significant medical problem, although none of these properties actually confers
increased virulence to the bacterium. These provide the opportunity for resistant
bacteria to proliferate and produce other virulence factors in animal patients
which are under treatment with an inappropriate antibiotic.
Several bacterial toxins are enzymes (cholera toxin, diphtheria
toxin, Pseudomonas exotoxin A and pertussis toxin) are NAD+ glycohydrolases
that also act as ADP-ribosyl-transferases. The toxic effect of these bacterial
enzymes on the host is integral to the pathogenesis of bacterial infections, but
the function of the enzymes in the normal bacterial physiology is not known. The
toxicity of these substances is “unintentional” as far as the bacteria are
concerned, considering that the primary goal of the microorganisms is to acquire
nutrients and multiply rather than to harm the host.

Host-mediated basis for bacterial virulence

Host-mediated pathogenesis is significant in certain infections
(tuberculosis). Damage in tissues are described as the results of the toxic
mediators released by lymphoid cells rather than from bacterial toxins. The
tissue damage in these infections is caused by toxic factors released from the
lymphocytes, macrophages and poly-morphonuclear neutrophils infiltrating the
site of infection. Often the host response is so intense that host tissues are
destroyed, allowing bacteria to proliferate (absence of a cellular response
to Mycobacterium leprae allows the bacteria to multiply to large numbers in the
skin that they become tightly packed and replace healthy tissue). The molecular
basis for bacterial virulence or the specific immune anergy is poorly understood.

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Enhancement of virulence by the intracellular growth of pathogens

Another factor that contributes to virulence is the ability of bacteria to

grow intracellularly (intracellular growth). This is common in some bacteria
(Rickettsia species) that grow only within eukaryotic cells. Other bacteria
(Salmonella species) invade cells but do not require them for growth. Other
pathogenic bacteria multiply in tissue fluids of host cells and exert pathogenic
effects in those locations.

Bacteria that enter and survive within eukaryotic cells are shielded from
humoral antibodies and can be eliminated only by a cellular immune response.
These bacteria possess specialized mechanisms that protect them from the harsh
effects of the lysosomal enzymes encountered within the cell. Although some
bacteria (Rickettsia, Coxiella and Chlamydia) grow only inside host cells, others
(Salmonella, Shigella, and Yersinia) are facultative intracellular pathogens,
invading cells when it gives them a selective advantage in the host.

Some bacteria survive the intra-cellular milieu by producing

phospholipases to dissolve the phagocytic vesicle surrounding them (R. rickettsi)
which destroys the phagosomal membrane with which the lysosomes fuse. Some
prefer the intracellular environment of macrophages for growth (Legionella
pneumophila) which induces its own uptake and blocks lysosomal fusion by
undefined mechanisms. Other bacteria have evolved to the point that they prefer
the low-pH environment within the lysosomal granules (Coxiella
burnetii). Salmonella and Mycobacterium species also appear to be very resistant
to intracellular killing by phagocytic cells, but their mechanisms of resistance
are not yet fully understood. Certainly, the capacity of bacteria to survive and
multiply within host cells has great impact on the pathogenesis of the respective
infections. Most bacterial pathogens do not invade cells but proliferate instead
in the extracellular environment enriched by body fluids.

Some bacteria (V. cholerae and Bordetella pertussis) do not even penetrate
body tissues but adhere to epithelial surfaces and cause disease by secreting
potent protein toxins. Non-invasive bacteria (E. coli and P. aeruginosa) frequently
spread rapidly to various tissues after gaining access to the body.

Bacterial infectivity
Factors produced by a microorganism to induce infections are called
virulence factors. These include toxins, surface coats that inhibit phagocytosis
and surface receptors that bind to host cells. Most frank or primary bacterial
pathogens have evolved with specific virulence factors that allow them to
multiply in their host or vector without being killed or expelled by the host
defenses. Many virulence factors are produced only by specific virulent strains
of a microorganism.

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Virulence factors are not considered independent of the host defenses

because the clinical course of a disease often depends on the interaction of
virulence factors with the host response. An infection begins when the balance
between bacterial pathogenicity and host resistance is upset. Animals and
humans live in an environment that favors microbial growth which far exceeds
that of most eukaryotic cells. Bacteria are probably more versatile than
eukaryotic cells in substrate utilization and biosynthesis. The high mutation rate
of bacteria combined with their short generation time results in rapid production
of the best-adapted strains and species. In general, bacteria are much more
resistant to toxic components in the environment than eukaryotic cells,
particularly when the major barriers of eukaryotes (skin and mucous
membranes) are breached.
From a real standpoint, bacteria can be said to have a single objective and
that is to multiply. The most highly evolved or adapted pathogens are those that
acquire the necessary nutritional substances for growth, disseminate with the
smallest expenditure of energy and least damage to the host. Some bacteria that
are poorly adapted to the host can synthesize virulence factors (tetanus and
diphtheria toxin) that are potent and threatens the life of the host. Virulence
factors help bacteria to (1) invade the host, (2) cause disease and (3) evade host
defenses.

Fig. 1. Cellular origin of bacterial virulence factors

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Functional types of virulence factors in bacteria

1. Adherence and colonization factors

To initiate infection, adherence to a mucosal surface is a requirement for
many bacterial pathogens. For example, the alimentary tract mucosa is
continually cleansed by the release of mucus from goblet cells and by the
peristaltic flow of the gut contents over the epithelium. Similarly, ciliated cells in
the respiratory tract sweep mucus and bacteria upward. In addition, the
turnover of epithelial cells at these surfaces is fairly rapid. The intestinal
epithelial cell monolayer is continually replenished and the cells are pushed from
the crypts to the villar tips in about 48 hours. To establish an infection at such
a site, the attaching pathogen multiplies before the release of mucus from goblet
cells and extruded epithelial cells are swept away.
Adherence/Attachment mechanisms in bacteria
a. Pili (fimbriae) and colonization factors that recognize and attach the
bacteria to cells. Many pathogenic bacteria colonize mucosal sites by
using pili (fimbriae) to adhere to cells. Some examples of piliated, adherent
bacterial pathogens are V. cholerae, E. coli, Salmonella spp., N.
gonorrheae, N. meningitidis and Streptococcus pyogenes.

2. Invasion factors
The ability of a bacterium to invade host cells is facilitated by the entry of
bacterium at mucosal surfaces. Surface components reportedly allow bacteria to
invade host cells and these components are encoded on bacterial plasmids and
on the chromosome.
Some invasive bacteria (obligate intracellular pathogens such
as Rickettsia and Chlamydia species) are facultative intracellular pathogens. The
specific bacterial surface factors that mediate invasion are still not known
although multiple gene products are reportedly involved.
Invasion factors are associated with Shigella and these are encoded on a
140 megadalton plasmid. Conjugation of the plasmid into E. coli gives the non-
invasive E. coli the capacity to invade cells. Other invasion genes have also
recently been identified in Salmonella spp. and Yersinia pseudotuberculosis. The
invasiveness of Rickettsia and Chlamydia species are known by many scientists
but the mechanisms of invasion are not fully understood.

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3. Capsules and other surface components

Bacterial capsule has been recognized as a protective mechanism for
bacteria. Many bacteria are surrounded by capsules that protect them from
opsonization and phagocytosis. Encapsulated strains of many bacteria
(pneumococci) are more virulent and more resistant to phagocytosis and
intracellular killing than non-encapsulated bacterial strains.
The amount and composition of capsular antigens and the structure of
lipopolysaccharide is known to be related to serum resistance. Capsulated
pathogenic pathogens associated with bacteremia are less affected to killing by
fresh human serum-containing complement components (serum resistant) than
other bacteria.
The relationship between surface structure and virulence is recognized
in Borrelia infections. As these bacteria encounter an increasing specific
immune response from the host, the bacterial surface antigens are reportedly
altered by mutation and the progeny that are no longer recognized by the
immune response express renewed virulence.
Salmonella typhi and some paratyphoid organisms carry a surface antigen
(Vi antigen) which is thought to enhance virulence. This antigen is composed of
a polymer of galactosamine and uronic acid in 1,4-linkage. Its role in virulence
has not been defined but it reportedly causes antibodies to become protective to
Salmonella infections.
Surface components of some bacteria have the ability to survive and
multiply inside phagocytic cells. A classic example is Mycobacterium tuberculosis
which survives host cells which is reportedly linked to the structure and
composition of its cell surface. A parasite (Toxoplasma gondii) has the
remarkable ability to block the fusion of lysosomes with the phagocytic vacuole.
The hydrolytic enzymes contained in the lysosomes are incapable to contribute
to the destruction of the parasite. The mechanisms by which bacteria like
Brucella abortus, Listeria monocytogenes and Legionella pneumophila remain
immobilized inside phagocytes are not understood.
4. Endotoxins
Endotoxins also known as lipopolysaccharides (LPS) are
large molecules that consist of a lipid and a polysaccharide containing O-
antigen, outer core and inner core joined by a covalent bonds.
Lipopolysaccharides are found in the outer membrane of Gram-negative
bacteria. The lipopolysaccharide or endotoxins on Gram-negative bacteria cause
fever, changes in blood pressure, inflammation, lethal shock and many other
toxic events.

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The term endotoxin was coined in 1893 by Pfeiffer to distinguish the class
of toxic substances released after lysis of bacteria from the toxic substances
(exotoxins) secreted by bacteria. Few other microbial products have been studied
as bacterial endotoxins. Endotoxins possess important biologic effects on hosts
and these have been subjects of intense investigation
Structure of endotoxins (lipopolysaccharides)
Endotoxin is a molecular complex of lipid and polysaccharide which
gave its alternate name as lipopolysaccharide. The complex is secured to
the outer membrane by ionic and hydrophobic forces and its strong
negative charge is neutralized by Ca2+ and Mg2+ ions.
Enough data on endotoxin from other Gram-negative organisms
have been reported to describe a common pattern with genus and species
diversity. Endotoxin molecules are reportedly similar in chemical structure
and biologic activity but some diversity has evolved. The molecular
complex is reportedly divided into 3 regions:
(1) O-specific chains which consist of a variety of repeating
oligosaccharide residues (O-antigen)
(2) Core polysaccharide forms the backbone of the macromolecule and is
responsible for antigenic diversity (inner and outer core)
(3) Lipid A is composed of a glucosamine disaccharide with attached
long-chain fatty acids and phosphate and this moiety confers toxicity to
endotoxin.

Fig. 2. Structural components of a bacterial endotoxin

Members of the family Enterobacteriaceae exhibit O-specific chains

of various lengths while N. gonorrhoeae, N. meningitidis and B.
pertussis contain only core polysaccharide and lipid A. Some investigators

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working on the latter forms of endotoxin call these lipo-oligosaccharides to

emphasize the chemical difference of these endotoxins from the endotoxin
of enteric bacilli.
Biologic activity of endotoxin
The biologic effects of endotoxin have been extensively studied.
These events can reportedly culminate in sepsis and lethal shock. The
more toxic effects include:
1. pyrogenicity
2. leukopenia followed by leukocytosis
3. complement activation
4. depression in blood pressure
5. mitogenicity
6. induction of prostaglandin synthesis
7. hypothermia

Biologic activities of the Lipid A component of endotoxin

1. mitogenic effects on B lymphocytes that increase resistance to viral
and bacterial infections
2. induction of gamma interferon production by T lymphocytes which
may enhance the antiviral state, promote rejection of tumor cells and
activate macrophages and natural killer cells
3. activation of the complement cascade with the formation of C3a and
C5a
4. induction of the formation of interleukin-1 by macrophages and
interleukin-2 and other mediators by T lymphocytes.

Current research focuses on exploiting the potential beneficial

effects of “nontoxic” endotoxin derivatives which holds promise for
development of future treatment regimens. For example, reports describe
that the toxicity of lipid A is reportedly reduced after hydrolysis of a
phosphate group or de-acylation of one or more fatty acids from the lipid
A molecule. Clinical trials are reportedly in progress in testing a mono-
phosphoryl lipid A for its potential in inducing low dose tolerance to
endotoxin. Tolerance to endotoxin is reportedly achieved by pre-treatment
of an animal with low doses of endotoxin or a detoxified lipid A derivative
before challenge with high doses of endotoxin. Experimental studies have
demonstrated that induction of tolerance to endotoxin reduces the
dangerous effects of endotoxin.
Endotoxin which largely accumulates in the liver following injection
of a sublethal dose can be devastating because of its ability to affect a

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variety of cell and host proteins. Kupffer cells, granulocytes, macrophages,

platelets and lymphocytes all have a cell receptor on their surface called
CD14 which binds endotoxin. Endotoxin binding to the CD14 receptor on
macrophages is enhanced by interaction with a host protein made in the
liver (i.e. LPS-binding protein). The extent of involvement of each cell type
probably depends on the level of endotoxin exposure. The effects of
endotoxin on such a wide variety of host cells reportedly result in a
complex array of host responses that can culminate in the serious
condition Gram-negative sepsis which often leads to shock and death.
The effects of endotoxin on host cells are known to stimulate
prostaglandin synthesis and to activate the kallikrein system (the kinin
system), the complement cascade via the alternative pathway, the clotting
system and the fibrinolytic pathways. When these normal host systems
are activated and operate out of control, endotoxin can be lethal. It is
difficult to comprehend the mechanisms of all cell responses and the
myriad sequelae of cell mediators released in the host following exposure
to endotoxin. Scientists recognize that the host cellular response to
endotoxin plays the major role in causing tissue damage rather than a
direct toxic effect of endotoxin.
Detection of endotoxin
Endotoxin is omnipresent in the environment. Solutions for human
or veterinary use are prepared under carefully controlled conditions to
ensure sterility and to remove endotoxin. Representative samples of every
manufacturing batch are checked for endotoxin by the Limulus lysate test
or the rabbit pyrogenicity test. This is a simple, fast and sensitive test
which is based on the ability of endotoxin to induce gelation of lysates of
amebocyte cells from the horseshoe crab Limulus polyphemus. It can be
used for rapid detection of certain Gram-negative infections (in the
cerebrospinal fluid).
5. Exotoxins
Exotoxins are protein toxins released from viable bacteria. These form a
class of potent poisons. Most of the higher molecular-sized exotoxin proteins are
heat-labile while numerous low molecular-sized exotoxins are heat-stable
peptides. Exotoxins are produced by a majority of Gram-positive while some
studies have described the release of exotoxin in a few Gram-negative bacteria.
The functions of exotoxins for the bacteria are usually unknown and the
genes for most can be deleted with no noticeable effect on bacterial growth. In
contrast to the extensive systemic and immune-system effects of endotoxin on
the host, the site of action of most exotoxins is more localized and is confined to
particular cell types or cell receptors. Tetanus toxin, for example, affects only
internuncial (neck region) neurons.

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Exotoxins can be grouped into several categories (such neurotoxins,

cytotoxins and enterotoxins) based on their biologic effect on host cells.
1. Neurotoxins (botulinum toxin formed by C. botulinum)
This potent neurotoxin acts on motor neurons by preventing the
release of acetylcholine at the myoneural junctions thereby preventing
muscle excitation and producing flaccid paralysis.
2. Cytotoxins (diphtheria toxin produced by Corynebacterium diphtheriae)

Cytotoxins constitute a larger, more heterogeneous grouping with a

wide array of host cell specificities and toxic manifestations. The
diphtheria cytotoxin inhibits protein synthesis in many cell types by
catalyzing the ADP-ribosylation of elongation factor II.

3. Enterotoxins (shiga-like enterotoxin from E. coli and cholera toxin)

Enterotoxins stimulate hypersecretion of water and electrolytes from

the intestinal epithelium to produce watery diarrhea. Some enterotoxins
are described as cytotoxic (shiga-like enterotoxin from E. coli) while others
perturb eukaryotic cell functions and are cytotonic (cholera toxin).
Enterotoxins can disturb normal smooth muscle contraction, causing
abdominal cramping and decrease transit time for water absorption in the
intestines. Enterotoxigenic E. coli and V. cholerae produce diarrhea after
attaching to the intestinal mucosa where enterotoxins are elaborated. E.
coli elaborate enterotoxins and reportedly acquired an invasion plasmid
which enhances its invasive character in intestinal mucosa.

Cholera toxin and E. coli heat-labile enterotoxins I and II reportedly

cause ADP-ribosylation of cell proteins in a manner similar to diphtheria
toxin resulting in increased levels of cyclic 3′,5′-adenosine monophosphate
(cAMP). The organisms responsible for shigellosis (Shigella dysenteriae, S.
boydii, S. flexneri and S. sonnei) reportedly penetrate the mucosal surface
of the colon and terminal ileum to proliferate and cause ulcerations that
bleed into the intestinal lumen. Despite causing extensive ulceration of the
mucosa, the pathogens rarely enter the bloodstream. The Shiga
enterotoxin produced by Shigella species and the Shiga-like enterotoxin
elaborated by many isolates of E. coli inhibit protein synthesis in
eukaryotic cells. It is not clear how the cytotoxic enterotoxin causes
hypersecretion of water and electrolytes from the intestinal epithelium.
These enterotoxins differ from those secreted by V. cholerae and E. coli in
that the Shiga toxins are cytotoxic and lethal, whereas the cholera toxin-
like enterotoxins are not. The latter enterotoxins cause no structural
damage to cells and are described as cytotonic. The ensuing inflammatory
response to the invading bacteria and their toxins appears to activate

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neurologic control mechanisms (release of prostaglandins and serotonin)

that normally regulate water and electrolyte transport.

6. Siderophores
Siderophores are iron-binding factors that allow some bacteria to compete
with the host for iron which is bound to hemoglobin, transferrin and
lactoferrin. Both animals and bacteria require iron for metabolism and growth
and the control of this limited resource is often used as an approach in the
conflict between pathogen and host. Animals have evolved mechanisms of
“withholding” iron from tissue fluids in an attempt to limit the growth of invading
bacteria. Although blood is a rich source of iron, this iron is not readily available
to bacteria since it is not free in solution. Most of the iron in blood is bound
either to hemoglobin in erythrocytes or to transferrin in plasma. Similarly, the
iron in milk and other secretions (tears, saliva, bronchial mucus, bile and
gastrointestinal fluid) is bound to lactoferrin. Some bacteria express receptors
for eukaryotic iron-binding proteins (like transferrin-binding outer membrane
proteins on the surface of Neisserira spp.). By means of these specialized
receptors, iron acquisition is facilitated thus providing the essential element for
bacterial growth.
Other bacteria have developed complex mechanisms to extract iron from
host proteins. Siderophores are substances produced by many bacteria to
capture iron from the host. The absence of iron triggers transcription of the genes
coding for the enzymes that synthesize siderophores and for a set of surface
protein receptors that recognize siderophores carrying bound iron. The binding
of siderophores for iron is reportedly robust or dense that even iron bound to
transferrin and lactoferrin is confiscated and taken up by the bacterial
cells. An example of a bacterial siderophore is enterochelin produced
by Escherichia and Salmonella species.
Experiments have demonstrated that Salmonella mutants that have lost
the capacity to synthesize enterochelin lose virulence in an assay of lethality in
mice. Injection of purified enterochelin along with the Salmonella mutants
restores virulence of the bacteria. Therefore, siderophore production by many
pathogenic bacteria is considered an important virulence mechanism.
Competition between host cells and bacterial pathogens for iron illustrates the
importance of siderophores. Since free iron is scarce in tissue fluids and blood,
bacterial siderophores compete effectively for Fe3+ bound to lactoferrin and
transferrin.

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Fig. 3. Iron-limiting activities of siderophore

7. Extracellular enzymes and activators associated to bacterial virulence

a. Alpha toxin hydrolyzes lecithinase and possesses hemolytic and

necrotic effects. This is produced by Clostridium perfringens.

b. Hyaluronidase hydrolyzes the ground substance (hyaluronic acid) in

connective tissues. This is also known as a spreading factor because
it hastens bacterial invasion by reducing viscosity of animal cell
membranes and facilitates formation of salts with protein aggregates
within cells. It is produced by pathogenic species of Staphylococcus
and Streptococcus spp.

c. Coagulase is an enzyme that increases the rate of plasma clotting

around an area of infection and provides a mechanical barrier to
phagocytes. This is produced by pathogenic Staphylococcus aureus.

d. Streptokinase is an enzyme that prevents walling-off of infecting

bacteria. It is produced by pathogenic Streptococcus spp.

e. Hemolysin brings about lysis of RBC and WBC. It is produced by

pathogenic Streptococcus spp

f. Proteinase is an enzyme which hydrolyzes muscle collagen and

proteins. It also causes dissolution of tissues and participates in the
formation of gas gangrene. This is produced by Clostridium
perfringens.

g. Cord factor is a virulence factor isolated and identified as a lipid

material at the cell surface of Mycobacterium tuberculosis. Its removal

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with the use of ideal extracting solvents renders the bacterium

avirulent.

h. Extracellular deoxyribonucleases of Streptococci

i. Aggressins, invasins, necrotizing toxins, leukocidins and allergenic

factors

Many factors determine the outcome of the bacterium-host relationship.

The host has to live in an environment filled with a diverse population of
microorganisms. Research efforts that identify and characterize the virulence
factors of pathogenic bacteria may open new ideas by on how to alter the
pathogenic mechanisms of virulent bacteria. The availability of an array of
antibiotics and vaccines has provided the medical profession with powerful tools
to control or cure many infections. Unfortunately, drugs have dwindled in their
capacity to completely eliminate bacterial infections both in human and animal
populations which highlights reported issues on drug resistance in the medical
field.
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Evaluation
1. Describe the role of virulence factors in infection.

2. Differentiate the nature and functions of endotoxin from exotoxin.

3. Explain the importance siderophores in iron acquisition by bacteria.

References
Peterson JW. Bacterial Pathogenesis. https://www.google.com/
search?q=7Bacterial+Pathogenesis+Johnny+W.+Peterson.&oq=7Bacterial+Path
ogenesis+Johnny+W.+Peterson.
Garcia GG, KK Amoako, DL Xu, T Inoue, Y Goto, T Shinjo. 1999. Chemical
composition of endotoxins produced by Fusobacterium necrophorum subsp.
necrophorum and F. necrophorum subsp. funduliforme. Microbios. 100 (397):
175-9.
Iglewski BH. 1990. Molecular basis of bacterial pathogenesis. Clark VL (eds):
The Bacteria: A Treatise on Structure and Function. Vol. XI. Academic Press,
Orlando, FL.

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