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 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 Pathogenesis
of of bacterial bacterial infection infection
Humans and animals have abundant normal
microflora.
Most bacteria do not produce disease but
achieve a balance with the host that ensures 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 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 Koch s s postulates postulates are are summarized summarized as 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 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 Koch s s postulates postulates remain remain a a
mainstay mainstay of of microbiology microbiology
However However, , since since the the late late 19th 19th century century, many , many
microorganisms microorganisms that that do not do not meet meet the the criteria criteria of of
the the postulates postulates have have been been shown shown to cause to cause
disease disease.. disease disease..
For For example example, , Treponema Treponema pallidum pallidum ((syphilis syphilis) )
and and Mycobacerium Mycobacerium leprae leprae ((leprosy leprosy) ) cannot cannot be be
grown grown in in vitro vitro, , but but there there are are animal animal models models of of
infection infection with with these these agents agents..
In In another another example example, , Neisseria Neisseria gonorrhoeae gonorrhoeae
((gonorrhea gonorrhea), ), there there is is no no animal animal model model of of
infection infection even even though though the the bacteria bacteria can can readily readily
be be cultivated cultivated in in vitro vitro..
The The host host s s immune immune responses responses should should be be
considered considered when when an an organism organism is is being being
investigated investigated as as the the possible possible cause cause of of a a disease disease..
Thus Thus, , development development of of a a rise rise in in specific specific antibody antibody
during during recovery recovery from from disease disease is is an an important important
adjunct adjunct to Koch to Koch s s postulates postulates..
Modern Modern--day day microbial microbial genetics genetics has has opened opened new new
frontiers frontiers to study to study pathogenic pathogenic bacteria bacteria and and differentiate differentiate
them them from from non non--pathogens pathogens. .
The The ability ability to study to study genes genes associated associated with with virulence virulence
has led to a has led to a proposed proposed of of Koch Kochs s postulates postulates::
The phenotype, or property, under investigation
should be associated with pathogenic members of a 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 Analysis of of infection infection and and disease disease through through the the
application application of of principles principles such as Koch such as Koch s s postulates postulates
leads leads to to classification classification of of bacteria bacteria as as pathogenic pathogenic or or
non non--pathogenic pathogenic..
Some Some bacterial bacterial species are species are always always considered considered to to be be
pathogens pathogens, , and and their their presence presence is is abnormal abnormal. .
Examples Examples include include Mycobacterium Mycobacterium tuberculosis tuberculosis Examples Examples include include Mycobacterium Mycobacterium tuberculosis tuberculosis
((tuberulosis tuberulosis) ) and and Yersinia Yersinia pestis pestis ((plague plague). ).
Other Other species are species are commonly commonly part part of of the the normal normal flora flora
of of humans humans ((and and animals animals) ) but but can can also also frequently frequently
cause cause disease disease. . For For example example, , Escherichia Escherichia coli coli is is part part
of of the the gastrointestinal gastrointestinal flora flora of of normal normal humans humans, , but but it it
is is also also a a comon comon cause cause of of urinary urinary tract tract infection infection, ,
traveller traveller s s diarrhea diarrhea, , and and other other diseases diseases..
The The infectious infectious process process
Infection Infection indicates indicates multiplication multiplication of of
microorganisms microorganisms..
Prior to Prior to multiplication multiplication, , bacteria bacteria (in case (in case of of
bacterial bacterial infection infection) ) must must enter enter and and establish establish bacterial bacterial infection infection) ) must must enter enter and and establish establish
themselves themselves within within the the host. host.
The The most most frequent frequent portals portals of of entry entry are are the the
respiratory respiratory ((mouth mouth and and nose), nose), gastrointestinal gastrointestinal, ,
and and urogenital urogenital tracts tracts. . Abnormal Abnormal areas areas of of
mucous mucous membranes membranes and and skin ( skin (e.g e.g. . cuts cuts, , burns burns) )
are are also also frequent frequent sites sites of of entry entry..
The The infectious infectious process 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 The infectious infectious process 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 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 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 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 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 Bacterial virulence virulence factors factors
Many factors determine the
virulence of bacteria, or their
ability to cause infection and ability to cause infection and
disease.
Toxins Toxins
Toxins produced by bacteria are
generally classified into two
groups: groups:
exotoxins
endotoxins
Endotoxins Endotoxins of of
gram gram--negative negative bacteria bacteria
The endotoxins of gram-negative bacteria
are complex lipopolysaccharides derived
from bacterial cell walls and are often 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 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 Corynebacterium diphtheriae diphtheriae strains strains that that
carry carry a a temperate temperate bacteriophage bacteriophage with with the the
structural structural gene gene for for the the toxin are toxin are toxigenic toxigenic
and and produce produce diphtheria diphtheria toxin. toxin. and and produce produce diphtheria diphtheria toxin. toxin.
This This native native toxin toxin is is enzymatically enzymatically
degraded degraded into into two two fragments fragments: A : A and and B, B,
linked linked together together by a disulfide by a disulfide bound bound. . Both Both
fragments fragments are are necessary necessary for for toxin toxin activity activity..
Tetanospasmin (toxin of Clostridium tetani)
Clostridium Clostridium tetani tetani is is an an anaerobic anaerobic gram gram- -positive rod positive rod that that is is
widespread widespread in in the the environment environment. .
Clostridium Clostridium tetani tetani contaminates contaminates wounds wounds, , and and the the spores spores
germinate germinate in in the the anaerobic anaerobic environment environment of of the the devitalized devitalized
tissue tissue. . The The vegetative vegetative forms forms of of Clostridium Clostridium tetani tetani produce produce tissue tissue. . The The vegetative vegetative forms forms of of Clostridium Clostridium tetani tetani produce produce
toxin toxin tetanospasmin tetanospasmin. . The The released released toxin has toxin has two two peptides peptides
linked linked by disulfide by disulfide bounds bounds. Toxin . Toxin reaches reaches the the central central
nervous nervous system system by by retrograde retrograde transport transport along along axons axons and and
through through the the systemic systemic circulation circulation. . The The toxin toxin acts acts by by
blocking blocking release release of of an an inhibitory inhibitory mediator mediator in motor neuron in motor neuron
synapses synapses. . The The result result is is initially initially localized localized then then generalized generalized, ,
muscle muscle spasms spasms. . Extremely Extremely small small amount amount of of toxin toxin can can be be
lethal lethal for for humans humans..
Botulotoxin (toxin of Clostridium botulinum)
Clostridium Clostridium botulinum botulinum is is found found in in soil soil or or water water and and may may
grow grow in in foods foods if if the the environment environment is is appropriately appropriately
anaerobic anaerobic..
An An exceedingly exceedingly potent potent toxin toxin ((the the most most potent potent toxin toxin known known) )
is is produced produced by by Clostridium Clostridium botulinum botulinum strains strains.. It It is is heat heat- - is is produced produced by by Clostridium Clostridium botulinum botulinum strains strains.. It It is is heat heat- -
labile labile and and is is destroyed destroyed by by sufficient sufficient heating heating.. There There are are
eight eight disctinct disctinct serological serological types types of of toxin toxin.. Types Types A, A, B B and and E E
are are most most commonly commonly associated associated wih wih human human disease disease.. Toxin Toxin
is is absorbed absorbed from from the the gut gut and and carried carried to to motor motor nerves nerves,,
where where it it blocks blocks the the release release of of acetylcholine acetylcholine at at synapses synapses
and and neuromuscular neuromuscular junctions junctions.. Muscle Muscle contraction contraction does does not not
occur occur,, and and paralysis paralysis results results..
Toxins of
Clostridium perfringens
Spores Spores of of Clostridium Clostridium perfringens perfringens are are introduced introduced
into into the the wounds wounds by by contamination contamination with with soil soil or or
faeces faeces. In . In the the presence presence of of necrotic necrotic tissue tissue ((an an
anaerobic anaerobic environment environment), ), spores spores germinate germinate and and
vegetative vegetative cells cells produce produce several several different different toxins toxins. . vegetative vegetative cells cells produce produce several several different different toxins toxins. .
Many Many of of these are these are necrotizing necrotizing and and hemolytic hemolytic and and
favour favour the the spread spread of of gangrene gangrene::
alpha alpha toxin toxin is is a a lecithinase lecithinase that that damages damages cell cell
membranes membranes
theta theta toxin toxin also also has a has a necrotizing necrotizing affect affect
and and other other
Streptococcal erythrogenic toxin
Some Some strains strains of of hemolytic hemolytic lysogenic lysogenic
streptococci streptococci produce produce a toxin a toxin that that results results in in
a a punctate punctate maculopapular maculopapular erythematous erythematous
rash rash, as in , as in scarlet scarlet fewer fewer. . rash rash, as in , as in scarlet scarlet fewer fewer. .
Production Production of of erythrogenic erythrogenic toxin toxin is is under under
the the genetic genetic control control of of temperate temperate
bacteriophage bacteriophage. . If If the the phage phage is is lost lost, , the the
streptococi streptococi cannot cannot produce produce toxin. toxin.
Toxic shock syndrom toxin - 1
(TSST-1)
Some Some Staphylococcus Staphylococcus aureus aureus strains strains growing growing on on
mucous mucous membranes membranes ((e.g e.g. on . on the the vagina in vagina in
association association with with menstruation menstruation), ), or or in in wounds wounds, ,
elaborate elaborate TSST TSST--1. 1. elaborate elaborate TSST TSST--1. 1.
This This toxin toxin is is associated associated with with toxic toxic shock shock syndrome. syndrome.
The The illness illness is is characterized characterized by by shock shock, , high high fewer fewer, ,
and and a a diffuse diffuse red red rash rash that that later later desquamates desquamates, ,
multiple multiple other other organs organs systems systems are are involved involved as as well well..
Exotoxins associated with
diarrheal diseases
Vibrio Vibrio cholerae cholerae toxin toxin
Staphylococcus Staphylococcus aureus aureus enterotoxin enterotoxin
Other Other enterotoxins enterotoxins -- enterotoxins enterotoxins are are also also
produced produced by by some some strains strains of of::
Yersinia Yersinia en entterocolitica erocolitica
Vibrio Vibrio parahaemolyticus parahaemolyticus
Aeromonas Aeromonas species species
Enzymes Enzymes
Many species Many species of of bacteria bacteria produce produce enzymes enzymes that that are not are not
intrinsically intrinsically toxic toxic but but play play important important role in role in the the infectious infectious
process process..
Collagenase Collagenase
degrades degrades collagen collagen, , the the major protein major protein of of fibrous fibrous
connective connective tissue tissue, , and and promotes promotes spread spread of of infection infection in in connective connective tissue tissue, , and and promotes promotes spread spread of of infection infection in in
tissue tissue..
Coagulase Coagulase
Staphylococccus Staphylococccus aureus aureus produce produce coagulase coagulase, , which which
works works in in conjuction conjuction with with serum serum factors factors to to coagulate coagulate
plasma. plasma. Coagulase Coagulase contributes contributes to to the the formation formation of of fibrin fibrin
walls walls around around staphylococcal staphylococcal lesions lesions, , which which helps helps them them
persist persist in in tissues tissues..
Enzymes Enzymes
Hyaluronidases Hyaluronidases
enzymes enzymes that that hydrolyze hydrolyze hyaluronic hyaluronic acid acid, a , a constituent constituent of of
the the ground ground substance substance of of connective connective tissue tissue. . They They are are
produced produced by by many many bacteria bacteria ((e.g e.g. . staphylococci staphylococci, ,
streptococci streptococci and and anaerobes anaerobes) ) and and aid aid in in their their spread spread
through through tissues tissues..
Streptokinase Streptokinase
many many hemolytic hemolytic streptococci streptococci produce produce streptokinase streptokinase
((fibrinolysin fibrinolysin), ), substance substance that that activates activates a a proteolytic proteolytic
enzyme enzyme of of plasma. plasma. This This enzyme, enzyme, also also called called
fibrinolysin fibrinolysin, , is is then then able able to to dissolve dissolve coagulated coagulated plasma plasma
and and probably probably aids in aids in the the spread spread of of streptococci streptococci through through
tissues tissues. . Streptokinase Streptokinase is is used used in in treatment treatment of of acute acute
myocardial myocardial infarction infarction to to dissolve dissolve fibrin fibrin clots clots..
Enzymes Enzymes
Hemolysins Hemolysins and and leukocidins leukocidins
Many Many bacteria bacteria produce produce substances substances that that are are
cytolysins cytolysins -- they they dissolve dissolve red red blood blood cells cells
((hemolysins hemolysins) ) or or kill kill tissue tissue cells cells or or leukocytes leukocytes ((hemolysins hemolysins) ) or or kill kill tissue tissue cells cells or or leukocytes leukocytes
((leukocidins leukocidins). ).
Streptolysin Streptolysin O, O, for for example example, , is is produced produced by by
group group A A streptococci streptococci and and is is letal letal for for mice mice and and
hemolytic hemolytic for for red red blood blood cells cells from from many many
animals animals..
Antiphagocytic Antiphagocytic factors factors
Many Many bacterial bacterial pathogens pathogens are are rapidly rapidly killed killed once once they they
are are ingested ingested by by polymorphonuclear polymorphonuclear cells cells or or
macrophages macrophages. .
Some Some pathogens pathogens evade evade phagocytosis phagocytosis or or leukocyte leukocyte
microbidical microbidical mechanisms mechanisms by by adsorbing adsorbing normal normal host host microbidical microbidical mechanisms mechanisms by by adsorbing adsorbing normal normal host host
componets componets to to their their surfaces surfaces. .
For For example example, , Staphylococcus Staphylococcus aureus aureus has has surface surface
protein A, protein A, which which binds binds to to the the Fc Fc portion portion of of IgG IgG. . Other Other
pathogens pathogens have have surface surface factors factors that that impede impede
phag phagoocytosis cytosis e.g e.g. . Streptococcus Streptococcus pneumoniae pneumoniae and and
many many other other bacteria bacteria have have polysaccharide polysaccharide capsules capsules..
Adherence Adherence factors factors
Once Once bacteria bacteria enter enter the the body body of of the the host, host, they they
must must adhere adhere to to cells cells of of a a tissue tissue surface surface. . If If they they
do not do not adhere adhere, , they they would would be be swept swept away away by by
mucus mucus and and other other fluids fluids that that bathe bathe the the tissue tissue
surface surface.. surface surface..
Adherence ( Adherence (which which is is only only one one step in step in the the
infect infectiious ous process process) ) is is followed followed by by development development
of of microcolonies microcolonies and and subsequent subsequent complex complex
steps steps in in the the pathogenesis pathogenesis of of infection infection..
Adherence Adherence factors factors
The The interactions interactions between between bacteria bacteria and and
tissue tissue cell cell surfaces surfaces in in the the adhesion adhesion
process process are are complex complex. .
Several Several factors factors play play important important role: role:
surface surface hydrophobicity hydrophobicity
binding binding molecules molecules on on bacteria bacteria and and host host
cell receptor cell receptor interaction interaction
and and other other