PATHOGENESIS

OF
BACTERIAL INFECTION
PATHOGENICITY
TOXIGENICITY
VIRULENCE
The pathogenesis of bacterial infection
includes the initiation of the infectious
process and the mechanisms leading to
the development of signs and symptoms
of bacterial disease.

The outcome of the interaction between

bacteria and host is determined by
characteristics that favour establishment
of the bacteria within the host and their
ability to damage the host as they are
opposed by host defense mechanisms.
Among the characterics of bacteria
are adherence to host cells,
invasiveness, toxigenity, and ability to
evade the host s immune system.

If the bacteria or immunological

reactions injure the host sufficiently,
disease becomes apparent.
 Pathogenesis
of bacterial infection
Humans and animals have abundant normal
microflora.
Most bacteria do not produce disease but
achieve a balance with the host that ensures
the survival, growth, and propagation of both
the bacteria and the host.
Sometimes bacteria that are clearly pathogens
(e.g. Salmonella typhi) are present, but infection
remains latent or subclinical and the host is a
"carrier" of the bacteria.
It can be difficult to show that a specific
bacterial species is the cause of a particular
disease.

In 1884, Robert Koch proposed a series of

postulates in his treatise on Mycobacterium
tuberculosis and tuberculosis.

These postulates have been applied more

broadly to link many specific bacterial species
with particular diseases.
Koch s postulates are summarized as follows
follows::

The microorganism should be found in all cases of the

disease in question, and its distribution in the body
should be in accordance with the lesions observed.
The microorganism should be grown in pure culture in
vitro (or outsite the body of the host) for several
generations.
When such a pure culture is inoculated into
susceptible animal species, the typical disease must
result.
The microorganism must again be isolated from the
lesions of such experimentally produced disease.
 Koch s postulates remain a
mainstay of microbiology
However, since the late 19th century
However, century,, many
microorganisms that do not meet the criteria of
the postulates have been shown to cause
disease..
disease

For example
example,, Treponema pallidum (syphilis
syphilis))
and Mycobacerium leprae (leprosy)
leprosy) cannot be
grown in vitro
vitro,, but there are animal models of
infection with these agents.
agents.
In another example,
example, Neisseria gonorrhoeae
(gonorrhea
gonorrhea),), there is no animal model of
infection even though the bacteria can readily
be cultivated in vitro.
vitro.

The host s immune responses should be

considered when an organism is being
investigated as the possible cause of a disease
disease..

Thus, development of a rise in specific antibody

Thus,
during recovery from disease is an important
adjunct to Koch s postulates
postulates..
 Modern-day microbial genetics has opened new
Modern-
frontiers to study pathogenic bacteria and differentiate
them from non
non--pathogens.
pathogens.
The ability to study genes associated with virulence
has led to a proposed of Koch
Koch´´s postulates:
postulates:
The phenotype, or property, under investigation
should be associated with pathogenic members of a
genus or pathogenic strains of a species.
Specific inactivation of the gene(s) associated with the
suspected virulence trait should lead to a measurable
loss in pathogenicity or virulence.
Reversion or allelic replacement of the mutated gene
should lead to restoration of pathogenicity.
Analysis of infection and disease through the
application of principles such as Koch s postulates
leads to classification of bacteria as pathogenic or
non--pathogenic.
non pathogenic.
Some bacterial species are always considered to be
pathogens,, and their presence is abnormal
pathogens abnormal..
– Examples include Mycobacterium tuberculosis
(tuberulosis)
tuberulosis) and Yersinia pestis (plague).
plague).
– Other species are commonly part of the normal flora
of humans (and animals
animals)) but can also frequently
cause disease.
disease. For example
example,, Escherichia coli is part
of the gastrointestinal flora of normal humans,
humans, but it
is also a comon cause of urinary tract infection,
infection,
traveller s diarrhea,
diarrhea, and other diseases
diseases..
 The infectious process
Infection indicates multiplication of
microorganisms..
microorganisms
Prior to multiplication
multiplication,, bacteria (in case of
bacterial infection
infection)) must enter and establish
themselves within the host.
The most frequent portals of entry are the
respiratory (mouth and nose), gastrointestinal
gastrointestinal,,
and urogenital tracts.
tracts. Abnormal areas of
mucous membranes and skin (e.g (e.g.. cuts
cuts,, burns
burns))
are also frequent sites of entry.
entry.
 The infectious process
Once in the body, bacteria must attach or
adhere to host cells, usually epithelial cells.
After the bacteria have established a primary
site of infection, they multiply and spread.
Infection can spread directly through tissues or
via the lymphatic system to bloodstream.
Bloodstream infection (bacteremia) can be
transient or persistent. Bacteremia allows
bacteria to spread widely in the body and
permits them to reach tissues particularly
suitable for their multiplication.
 The infectious process
As an example of the infectious process, Streptococcus
pneumoniae can be cultured from the nasopharynx of 5-40% of
healthy people.
Occasionally, S. pneumoniae strains from the nasopharynx are
aspirated into the lungs. Infection develops in the terminal air
space of the lungs in persons who do not have protective
antibodies against that type of S. pneumoniae. Multiplication of
S. pneumoniae strains and resultant inflammation lead to
pneumonia. The strains then enter the lymphatics of the lung
and move to the bloodstream. Between 10% and 20% of
persons with S. pneumoniae pneumonia have bacteremia at
the time the diagnosis of pneumonia is made. Once bacteremia
occurs, S. pneumoniae strains can spread to their preferred
secondary sites of infection (e.g. cerebrospinal fluid, heart
valves, joint spaces). The major resulting complications of S.
pneumoniae pneumonia include meningitis, endocarditis and
septic arthritis.
 Basic terms frequently used in
describing aspects of pathogenesis:
Infection
– Multiplication of an infectious agent within the
body.
– Multiplication of the bacteria that are part of
normal flora of gastrointestinal tract, skin, etc,
is generally not considered an infection.
– On the other hand, multiplication of
pathogenic bacteria (e.g. Salmonella
species), even if the person is asymptomatic,
is deemed an infection.
 Basic terms frequently used in
describing aspects of pathogenesis:
Pathogenicity
– The ability of an infectious agent to cause disease.

Virulence
– The quantitative ability of an agent to cause
disease.
– Virulent agents cause disease when introduced into
the host in small numbers.
– Virulence involves invasiveness and toxigenicity.
 Basic terms frequently used in
describing aspects of pathogenesis:
Toxigenicity
– The ability of a microorganism to produce a toxin
that contributes to the development of disease.

Invasion
– The process whereby bacteria, parasites, fungi and
viruses enter the host cells or tissues and spread in
the body.
 Basic terms frequently used in
describing aspects of pathogenesis:
Pathogen
– A microorganism capable of causing disease.

Non-pathogen
– A microorganism that does not cause disease. It may be part
of the normal flora.

Opportunistic pathogen
– An agent capable of causing disease only when the host s
resistance is impaired (e.g. the patient is
immunocompromised).
– An agent capable of causing disease only when spread from
the site with normal bacterial microflora to the sterile tissue
or organ.
Bacterial virulence factors
Many factors determine the
virulence of bacteria, or their
ability to cause infection and
disease.
 Toxins
Toxins produced by bacteria are
generally classified into two
groups:
–exotoxins
–endotoxins
 Endotoxins of
Gram--negative bacteria
Gram
The endotoxins of Gram-negative bacteria
are complex lipopolysaccharides derived
from bacterial cell walls and are often
liberated when the bacteria lyse.

The substances are heat-stable and can

be extracted (e.g. with phenol-water).
Pathophysiological effects of
endotoxins are similar regardless
of their bacterial origin:
– fever
– leukopenia
– hypotension
– impaired organ perfusion and acidosis
– activation of C3 and complement cascade
– disseminated intravascular coagulation
(DIC)
– shock, death
 Exotoxins
Many Gram-positive and Gram-
negative bacteria produce exotoxins
of considerable medical importance.

Some of these toxins have had major

role in world history (e.g. toxin of
Clostridium tetani).
 Diphtheria toxin
(toxin of Corynebacterium diphtheriae)
Corynebacterium diphtheriae strains that
carry a temperate bacteriophage with the
structural gene for the toxin are toxigenic
and produce diphtheria toxin.

This native toxin is enzymatically

degraded into two fragments
fragments:: A and B,
linked together by a disulfide bound.
bound. Both
fragments are necessary for toxin activity.
activity.
Tetanospasmin (toxin of Clostridium tetani)

Clostridium tetani is an anaerobic Gram

Gram--positive rod that is
widespread in the environment
environment..

Clostridium tetani contaminates wounds

wounds,, and the spores
germinate in the anaerobic environment of the devitalized
tissue.. The vegetative forms of Clostridium tetani produce
tissue
toxin tetanospasmin.
tetanospasmin. The released toxin has two peptides
linked by disulfide bounds
bounds.. Toxin reaches the central
nervous system by retrograde transport along axons and
through the systemic circulation
circulation.. The toxin acts by
blocking release of an inhibitory mediator in motor neuron
synapses.. The result is initially localized then generalized,
synapses generalized,
muscle spasms.
spasms. Extremely small amount of toxin can be
lethal for humans
humans..
Botulotoxin (toxin of Clostridium botulinum)

Clostridium botulinum is found in soil or water and may

grow in foods if the environment is appropriately
anaerobic..
anaerobic

An exceedingly potent toxin (the most potent toxin known) known)

is produced by Clostridium botulinum strainsstrains.. It is heat
heat--
labile and is destroyed by sufficient heating.
heating. There are
eight disctinct serological types of toxin
toxin.. Types A, B and E
are most commonly associated wih human disease. disease. Toxin
is absorbed from the gut and carried to motor nerves, nerves,
where it blocks the release of acetylcholine at synapses
and neuromuscular junctions
junctions.. Muscle contraction does not
occur,, and paralysis results
occur results..
 Toxins of
Clostridium perfringens
Spores of Clostridium perfringens are introduced
into the wounds by contamination with soil or
faeces.. In the presence of necrotic tissue (an
faeces
anaerobic environment),
environment), spores germinate and
vegetative cells produce several different toxins
toxins..

Many of these are necrotizing and hemolytic and

favour the spread of gangrene
gangrene::
– alpha toxin is a lecithinase that damages cell
membranes
– theta toxin also has a necrotizing affect
– and other
Streptococcal erythrogenic toxin
Some strains of hemolytic lysogenic
streptococci produce a toxin that results in
a punctate maculopapular erythematous
rash,, as in scarlet fewer
rash fewer..

Production of erythrogenic toxin is under

the genetic control of temperate
bacteriophage.. If the phage is lost
bacteriophage lost,, the
streptococi cannot produce toxin.
Toxic shock syndrom toxin - 1
(TSST-1)
Some Staphylococcus aureus strains growing on
mucous membranes (e.g.
e.g. on the vagina in
association with menstruation
menstruation),
), or in wounds
wounds,,
elaborate TSST
TSST--1.

This toxin is associated with toxic shock syndrome.

The illness is characterized by shock

shock,, high fewer
fewer,,
and a diffuse red rash that later desquamates
desquamates,,
multiple other organs systems are involved as well
well..
Exotoxins associated with
diarrheal diseases
Vibrio cholerae toxin
Staphylococcus aureus enterotoxin
Other enterotoxins - enterotoxins are also
produced by some strains ofof::
– Yersinia en
entterocolitica
– Vibrio parahaemolyticus
– Aeromonas species
 Enzymes
Many species of bacteria produce enzymes that are not
intrinsically toxic but play important role in the infectious
process..
process

Collagenase
– degrades collagen,
collagen, the major protein of fibrous
connective tissue
tissue,, and promotes spread of infection in
tissue..
tissue

Coagulase
– Staphylococccus aureus produce coagulase
coagulase,, which
works in conjuction with serum factors to coagulate
plasma. Coagulase contributes to the formation of fibrin
walls around staphylococcal lesions
lesions,, which helps them
persist in tissues.
tissues.
 Enzymes
Hyaluronidases
– enzymes that hydrolyze hyaluronic acid,
acid, a constituent of
the ground substance of connective tissue
tissue.. They are
produced by many bacteria (e.g
e.g.. staphylococci
staphylococci,,
streptococci and anaerobes
anaerobes)) and aid in their spread
through tissues.
tissues.

Streptokinase
– many hemolytic streptococci produce streptokinase
(fibrinolysin),
fibrinolysin), substance that activates a proteolytic
enzyme of plasma. This enzyme, also called
fibrinolysin,, is then able to dissolve coagulated plasma
fibrinolysin
and probably aids in the spread of streptococci through
tissues.. Streptokinase is used in treatment of acute
tissues
myocardial infarction to dissolve fibrin clots.
clots.
 Enzymes
Hemolysins and leukocidins
– Many bacteria produce substances that are
cytolysins - they dissolve red blood cells
(hemolysins
hemolysins)) or kill tissue cells or leukocytes
(leukocidins
leukocidins).
).
– Streptolysin O, for example,
example, is produced by
group A streptococci and is letal for mice and
hemolytic for red blood cells from many
animals..
animals
 Antiphagocytic factors
Many bacterial pathogens are rapidly killed once they
are ingested by polymorphonuclear cells or
macrophages..
macrophages

Some pathogens evade phagocytosis or leukocyte

microbidical mechanisms by adsorbing normal host
componets to their surfaces
surfaces..

For example,
example, Staphylococcus aureus has surface
protein A, which binds to the Fc portion of IgG.
IgG. Other
pathogens have surface factors that impede
phago
phag ocytosis e.g
e.g.. Streptococcus pneumoniae and
many other bacteria have polysaccharide capsules.
capsules.
 Adherence factors
Once bacteria enter the body of the host, they
must adhere to cells of a tissue surface
surface.. If they
do not adhere,
adhere, they would be swept away by
mucus and other fluids that bathe the tissue
surface..
surface

Adherence (which
(which is only one step in the
infectiious process)
infect process) is followed by development
of microcolonies and subsequent complex
steps in the pathogenesis of infection.
infection.
 Adherence factors
The interactions between bacteria and
tissue cell surfaces in the adhesion
process are complex.
complex.

Several factors play important role:

– surface hydrophobicity
– binding molecules on bacteria and host
cell receptor interaction
– and other