The document discusses the pathogenesis of bacterial infection, including how bacteria interact with the host and cause disease. It describes factors that determine bacterial virulence like toxins, invasiveness, and the ability to evade the immune system. The document outlines Koch's postulates for determining the causative agent of a disease and notes exceptions where these postulates do not always apply. It also summarizes some key terms used in pathogenesis like infection, pathogenicity, and virulence factors. Specific examples of bacterial toxins that contribute to disease are discussed.

1. PATHOGENESIS
OF
BACTERIAL INFECTION
PATHOGENICITY
TOXIGENICITY
VIRULENCE

2. 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.
.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.
.

8. 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.
.

9. 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
Koch´
´s
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.

10. 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.
.

11. 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.
.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. Toxins
Toxins
Toxins produced by bacteria are
generally classified into two
groups:
groups:
–exotoxins
–endotoxins

20. 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).

21. 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

22. 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).

23. 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.
.

24. 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.
.

25. 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.
.

26. 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

27. 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.

28. 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.
.

29. 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
ent
terocolitica
erocolitica
–
–Vibrio
Vibrio parahaemolyticus
parahaemolyticus
–
–Aeromonas
Aeromonas species
species

30. 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.
.

31. 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.
.

32. 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.
.

33. 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
phago
ocytosis
cytosis e.g
e.g.
. Streptococcus
Streptococcus pneumoniae
pneumoniae and
and
many
many other
other bacteria
bacteria have
have polysaccharide
polysaccharide capsules
capsules.
.

34. 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
infecti
ious
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.
.

35. 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