Bacterial Pathogenesis

*
*Koch’s Postulates
*General Terms Used In Pathogenesis
*Virulence Factors and its examples
*Super Antigen
*Infection and its types
*Mechanism Of Pathogenesis
*Transmission
*Adherence
*Invasion and inflammation
*Toxin Production
*Immuno-pathogenesis

*KOCH'S POSTULATES (MODIFIED)
*1. The organism must always be found in humans with the infectious
disease but not found in healthy ones.
*2. The organism must be isolated from humans with the infectious
disease and grown in pure culture.
*3. The organism isolated in pure culture must initiate disease when
re-inoculated into susceptible animals.
*4. The organism should be re-isolated from the experimentally
infected animals.
*Postulates 3. and 4. are extremely important in definite proof of
the role of agent in human disease. However, this depends on the
ability to develop animal models that resemble the human disease.
In many cases such models do not exist.

*General Terms Used In
Pathogenesis:A pathogen is a microorganism that is able to cause disease
in a plant, animal or insect.
Pathogenicity is the ability to produce disease in a host
organism. Microbes express their pathogenicity by means of
their virulence.
OR
Pathogenesis is a multi-factorial process which depends on
the immune status of the host, the nature of the species or
strain (virulence factors) and the number of organisms in the
initial exposure.
virulence, a term which refers to the degree of
pathogenicity of the microbe. Hence, the determinants of
virulence of a pathogen are any of its genetic or biochemical
or structural features that enable it to produce disease in a
host.

*Oppotunistic Pathogen:
*those that take advantage of certain situations
*usually do not cause disease in a healthy host, one with a
healthy immune system.
* A compromised immune system, however, presents an
"opportunity" for the pathogen to infect.
*Parasites:
*An organism that grows, feeds, and is sheltered on or in a
different organism while contributing nothing to the survival
of its host.
*Obligate Intra Celullar Parasite:
*cannot reproduce outside their host cell, meaning that the
parasite's reproduction is entirely reliant on intracellular
resources.e.g. Viruses and some bacteria i.e chlamydia and
rickettesia.

*Virulence factors :
These are molecules expressed and secreted by
pathogens (bacteria, viruses, fungi and protozoa) that
enable them to achieve the following:
colonization of a niche in the host (this includes
adhesion to cells)
* Immuno evasion, evasion of the host's immune
response
* Immunosuppression, inhibition of the host's immune
response
* entry into and exit out of cells (if the pathogen is
an intracellular one)
* obtain nutrition from the host.
*Pathogens possess a wide array of virulence factors.
Some are intrinsic to the bacteria (e.g. capsules and
endotoxin) whereas others are obtained from
plasmids (e.g. some toxins).

*
Examples Of Virulance Factors:
Examples of virulence factors for Staphylococcus aureus
are hyaluronidase, protease, coagulase, lipases,
deoxyribonucleases and enterotoxins.
*Some examples of virulence factors for Streptococcus
pyogenes are:
*M protein, lipoteichoic acid, hyaluronic acid capsule,
* invasins such as streptokinase, hyaluronidase, and
streptolysins, and exotoxins
*adhesion factors, extracellular enzymes, toxins and
antiphagocytic factors.

*Super antigen:
*Superantigens (SAgs) are a class of antigens which cause non-
specific activation of T-cells resulting in oligoclonal T cell
activation and massive cytokine release.
*produced by pathogenic microbes (including viruses,
mycoplasma, and bacteria)
*1. as a defense mechanism against the immune system.
*2. Compared to a normal antigen-induced T-cell response
where .001-.0001% of the body’s T-cells are activated,
*capable of activating up to 20% of the body’s T-cells.
*Anti-CD3 and Anti-CD28 Antibodies have also shown to be
highly potent superantigens (and can activate up to 100% of T
cells).

*1. Bind to TCR and activate T cells
*2. Autoimmune-like responses
*3. S. aureus =>Toxic shock syndrome toxin
* S. pyogenes=> Erythrogenic toxin A orC

*Colonization
*Colonization occurs whenever any one or more species
populate an area.
*derived from the Latin colere, "to inhabit, cultivate,
originally related to human.
*Infection:
*Infection: The growth of a parasitic organism within the
body.e.g. Bacteria
*A person with an infection has another organism (a "germ")
growing within him, drawing its nourishment from the person.

*Types Of Infections:
*Communicable Infection:
*An infection that can be transmitted from one individual to
another either directly by contact or indirectly by fomites
and vectors.
*Asymptomatic Infection:
*a disease is considered asymptomatic if a patient is a carrier
for a disease or infection but experiences no symptoms.
* A condition might be asymptomatic if it fails to show the
noticeable symptoms with which it is usually associated
*also called subclinical infections. The term clinically silent is
also used.

*Symptomatic Infection:
a disease is considered symptomatic if a patient is a carrier
for a disease or infection and express symptoms . e.g. fever.
Pandemic infection:
pandemic is an epidemic of infectious disease that is spreading
through human populations across a large region; for instance
multiple continents, or even worldwide. e.g. HIV
Epidemic infection:
an epidemic occurs when new cases of a certain disease, in a
given human population, and during a given period. e.g. dengue
in punjab.
Endemic infection:
Endemic infection Prevalent in or restricted to a particular
region, community, or group of people. e.g. cholera

Infection Results In :
1.carrier state:
* A carrier state occurs when someone has been exposed to a
pathogen (such as TB).
*A person may live as a carrier of a pathogen and would never
know it
*unless tested antibodies against the pathogen.it lives in the
host's body and can be passed on to others, without ever
actually causing measurable harm to the host.
2.latent state:
*In a latent state, the virus is simply "at rest".
*person infected with the pathogen will show signs of the
disease, at some time in the individual's life.
*common in many diseases,
*complimented by the "lytic" or active state of the pathogen/
disease.

*Mechanism Of Bacterial
Pathogenesis:
Two broad qualities of pathogenic bacteria underlie the
means by which they cause disease
*1. Invasiveness:
*It is the ability to invade tissues.
*encompasses mechanisms for colonization (adherence and initial
multiplication)
* production of extracellular substances which facilitate invasion
(invasins).

2. Toxigenesis:
*It is the ability to produce toxins. Bacteria may
produce two types of toxins called exotoxins and
endotoxins.
* Exotoxins:
* These are released from bacterial cells and
may act at tissue sites removed from the site of
bacterial growth.
* Endotoxins:
*These are cell-associated substance.
*released from growing bacterial cells and cells
that are lysed as a result of effective host
defense (e.g. lysozyme) or the activities of
certain antibiotics (e.g. penicillins and
cephalosporins).

*Determinants Of Pathogenesis:
1.Transmission.
2.Adhesion.
3.Invasion and Inflammation.
4.Toxin Production.
5.Immunopathogenesis.

*1.TRANSMISSION
Specific bacterial species (or strains within a species) initiate
infection after being transmitted by different routes to specific
sites in the human body.
Four major routes of transmission:
*1.Skin i.e. through cuts or wounds.
*2.Gastro intestinal tract i.e. by ingestion of food or water.
*3.Respiratory tract i.e.in airborne droplets.
*4.Genital Tract i.e. through sexual contact.
*
1.TRANSMISSION:

*Disease can be directly transmitted in two ways:
 Horizontal disease transmission – from one individual to
another in the same generation (peers in the same age
group).
* Horizontal transmission can occur by either
* direct contact (licking, touching, biting)
* indirect contact air – cough or sneeze
*(vectors or fomites that allow the transmission of disease
without physical contact).
 Vertical disease transmission – passing a disease causing
agent vertically from parent to offspring,
* such as perinatal transmission.

*Different Mode Of Pathogen
Transmission

TRANSMISSION THROUGH AEROSOLS:

*Adherence:
*The process or condition of attachment.
*Mechanisms of Adherence to Cell or Tissue Surfaces
*The mechanisms for adherence may involve two steps:
*1. nonspecific adherence: reversible attachment of the
bacterium to the eukaryotic surface (sometimes called
"docking")
*2. specific adherence: irreversible permanent attachment of
the microorganism to the surface (sometimes called
"anchoring").

*Possible interactions and forces involved are:
*1. hydrophobic interactions
*2. electrostatic attractions
*3. atomic and molecular vibrations resulting from fluctuating
dipoles of similar frequencies
*4. Brownian movement
*5. recruitment and trapping by biofilm polymers interacting
with the bacterial glycocalyx (capsule)

2. INVASION and Inflammation:
*The invasion of a host by a pathogen may be aided by the
production of bacterial extracellular substances which act
against the host by breaking down primary or secondary
defenses of the body. Medical microbiologists refer to these
substances as invasins.
* Most invasins are proteins (enzymes) that act locally to
damage host cells and/or have the immediate effect of
facilitating the growth and spread of the pathogen.
*The damage to the host as a result of this invasive activity
may become part of the pathology of an infectious disease.

*Inflammation:
*A basic way in which the body reacts to infection, irritation or
other injury, the key feature being redness, warmth, swelling
and pain.
*a type of nonspecific immune response.
*1.Pyogenic inflammation:
*Capable of generating pus.
*Neutrophils are predominant cells.
*Streptococcus, Staphocococcus, and bowel bacteria are the
primary pyogenic organisms.
*2.Granulomatous inflammation:
*usually chronic, marked by granuloma formation.
*Macrophages and T-cells are predominant.
*Most important is Mycobacterium Tuberculosis

*The extracellular proteins produced by bacteria which
promote their invasion are not clearly distinguished from
some extracellular protein toxins ("exotoxins") which also
damage the host.
*usually act at a short range (in the immediate vicinity of
bacterial growth) and may not actually kill cells as part of
their range of activity
* exotoxins are often cytotoxic and may act at remote sites
(removed from the site of bacterial growth). Also, exotoxins
typically are more specific and more potent in their activity
than invasins. Even so, some classic exotoxins (e.g. diphtheria
toxin, anthrax toxin) may play some role in colonization or
invasion in the early stages of an infection, and some invasins
(e.g. staphylococcal leukocidin) have a relatively specific
cytopathic effect.

*Bacterial Invasins:
Spreading Factors:
"Spreading Factors" is a descriptive term for a family of
bacterial enzymes that affect the physical properties of
tissue matrices and intercellular spaces, thereby promoting
the spread of the pathogen.
Hyaluronidase. is the original spreading factor. It is
produced by streptococci. staphylococci, and clostridia. The
enzyme attacks the interstitial cement ("ground substance")
of connective tissue by depolymerizing hyaluronic acid.e.g.
strept pyogenes.
Collagenase: is produced by Clostridium histolyticum and
Clostridium perfringens. It breaks down collagen, the
framework of muscles, which facilitates gas gangrene due to
these organisms.e.g. strept pyogenes.

Neuraminidase: is produced by intestinal pathogens such as
Vibrio cholerae and Shigella dysenteriae. It degrades
neuraminic acid (also called sialic acid), an intercellular
cement of the epithelial cells of the intestinal mucosa.
Streptokinase and staphylokinase :are produced by
streptococci and staphylococci, respectively. Kinase enzymes
convert inactive plasminogen to plasmin which digests fibrin
and prevents clotting of the blood. The relative absence of
fibrin in spreading bacterial lesions allows more rapid
diffusion of the infectious bacteria.

Enzymes. that Cause Hemolysis and/or Leucolysis
Phospholipases. produced by Clostridium perferingens (i.e.,
alpha toxin), hydrolyze phospholipids in cell membranes by
removal of polar head groups.
Lecithinases. also produced by Clostridium perferingens,
destroy lecithin (phosphatidylcholine) in cell membranes.
Hemolysins. notably produced by staphylococci (i.e., alpha
toxin), streptococci (i.e., streptolysin) and various clostridia,
may be channel-forming proteins or phospholipases or
lecithinases that destroy red blood cells and other cells (i.e.,
phagocytes) by lysis.
 Coagulase.
 Coagulase, formed by Staphylococcus aureus, is a cell-
associated and diffusible enzyme that converts fibrinogen to
fibrin which causes clotting.

Invasin Bacteria Involved Activity
Hyaluronidase
Streptococci,
staphylococci and
clostridia
Degrades hyaluronic of
connective tissue
Collagenase Clostridiumspecies
Dissolves collagen
framework of muscles
Neuraminidase
Vibrio
choleraeand Shigella
dysenteriae
Degrades neuraminic acid
of intestinal mucosa
Coagulase
Staphylococcus aureus Converts fibrinogen to
fibrin which causes
clotting
Some Extra Cellular Bacterial Proteins That Act As
Invasins:

Kinases
Staphylococci and
streptococci
Converts plasminogen to
plasmin which digests fibrin
Leukocidin Staphylococcus aureus
Disrupts neutrophil membranes
and causes discharge of
lysosomal granules
Streptolysin Streptococcus pyogenes
Repels phagocytes and disrupts
phagocyte membrane and
causes discharge of lysosomal
granules
Hemolysins
Streptococci,
staphylococci and
clostridia
Phospholipases or lecithinases
that destroy red blood cells
(and other cells) by lysis
Lecithinases Clostridium perfringens
Destroy lecithin in cell
membranes

Phospholipases
Clostridium perfringens
Phospholipases Clostridium
perfringens Destroy
phospholipids in cell
membrane.
Anthrax EF Bacillus anthracis
Anthrax EF Bacillus
anthracis One
component (EF) is an adenylate
cyclase which causes increased
levels of intracellular cyclic AMP
Pertussis AC Bordetella pertussis
Pertussis AC Bordetella
pertussisOne toxin component is
an adenylate cyclase that acts
locally producing an increase in
intracellular cyclic AMP
.

*
*Polypeptide in nature.
*Secreted by both gram positive and gram negative species.
*Induce high titer antibodies called antitoxins.
*Most toxic substance known.
*Toxoid used as vaccine.
*Can be divided into three categories:
*Cytotoxins
*Neurotoxins
*Enterotoxins

*Exotoxins:
*Many bacteria secrete proteins (exotoxins) that modify, by
enzymatic action, or otherwise destroy certain cellular
structures.
* Effects of exotoxins are usually seen acutely, since they are
sufficiently potent that serious effects (e.g. death) often
result. Examples of this are botulism, anthrax, cholera and
diphtheria.
* Classes of exotoxins include:
Toxins that act on the extracellular matrix of connective
tissue.
*e.g. Clostridium perfringens collagenase, Staphylococcus
aureus hyaluronidase.

Toxins that have a cell binding "B" component and an active
"A" enzymatic component (A-B type toxins)
*These include:
*a) Those with ADP-ribosylating activity e.g. cholera toxin, E.
coli heat labile toxin, Pseudomonas aeruginosa and diphtheria
toxins.
*b) Those with a lytic activity on 28S rRNA e.g. shiga and
shiga-like (vero) toxins.
*c) Those with a partially characterized site of action e.g.
botulinum toxin, tetanus toxin and anthrax lethal toxin.
Membrane Damaging Toxins e.g. Staphylococcus aureus delta
toxin

*Toxins which act extracellularly. These include proteases,
collagenases and hyaluronidases. For example, Clostridium
perfringens produces a potent collagenase, whilst
Staphylococcus aureus produces a hyaluronidase. Damage to
the connective tissue matrix (by hyaluronidase and
collagenase) can "loosen up" the tissue fibers allowing the
organism to spread through the tissues more readily. Also
included in this group is the exfoliatin of Staphylococcus
aureus which causes separation of the layers within the
epidermis and is the causative agent of scalded skin syndrome
in the newborn.
*A - B Toxins. Such toxins consist of two components. One
binds to cell surfaces and the other passes into the cell
membrane or cytoplasm where it acts. The classical toxins
demonstrated to act in this fashion are those of cholera and
diphtheria.

*(i) ADP-ribosylating exotoxins
*Diphtheria toxin (produced by Corynebacterium diphtheriae). The
toxin is synthesized as one polypeptide chain and readily nicked
into two chains held together by a disulfide bond. B binds to cells
and A has the enzymatic activity. A is endocytosed and from the
endosome passes into the cytosol. Diphtheria toxin ADP-ribosylates
elongation factor (EF2) in ribosomes, thus inhibiting protein
synthesis. Pseudomonas exotoxin A has an similar mode of action to
diphtheria toxin.
*Cholera toxin has several subunits which form a ring with one A
subunit inserted in the center. B binds to gangliosides on the cell
surface and appear to provide a channel through which A
penetrates. after internalization ADP-ribosylates a cell membrane
regulator complex (using NADH as a substrate), in turn causing
increase activation of adenylate cyclase. Activation of adenylate
cyclase causes an increase in cyclic AMP production with resulting
decrease in electrolytes

*(iii) Partially characterized site of action
*Botulinum neurotoxins, tetanospasmin and the lethal toxin of
B. anthracis appear to be A-B type exotoxins. Botulinum toxin
acts by causing inhibition of release of acetylcholine at the
neuromuscular junction. Tetanus toxin is taken up at
neuromuscular junctions and transported in axons to
synapses. Botulinal exotoxin, produced by Clostridium
botulinum .This causes a flaccid paralysis , a weakening of
the involved muscles. Death is usually from respiratory
failure. While two exotoxins of C. botulinum catalyze ADP-
ribosylation of host cell proteins, the botulinal toxin that
affects neurons does not. Since the botulinal toxin is able to
cause a weakening of muscles, it is now being used
therapeutically to treat certain neurologic disorders such as
dystonia and achalasia that result in abnormal sustained
muscle contractions, as well as a treatment to remove facial
lines.

*Tetanus Toxins:
*Tetanus exotoxin (tetanospasmin), produced by
Clostridium tetani . This is a neurotoxin that binds to
inhibitory interneurons of the spinal cord and blocks their
release of inhibitor molecules. The toxin, by blocking the
release of inhibitors, keeps the involved muscles in a
state of contraction and leads to spastic paralysis , a
condition where opposing flexor and extensor muscles
simultaneously contract. Death is usually from respiratory
failure.

*Membrane Damaging Toxins:
*These toxins enzymatically digest the phospholipid (or
protein) components of membranes or behave as detergents.
In each case holes are punched in the cell membrane and the
cytoplasmic contents can leach out. The phospholipase
("toxin") of C. perfringens is an example of a membrane
damaging toxin. It destroys blood vessels . This also helps
create an anaerobic environment which is important in the
growth of this strict anaerobe

*Endotoxins
Endotoxins are toxic components of the bacterial cell.
*Lipopolysaccharide in nature .
* peptidoglycan displays many endotoxin-like properties.
*Endotoxins are "non-specific" inciters of inflammation. For
example, cells of the immune system and elsewhere are
stimulated to release cytokines (including interleukin 1 and
tumor necrosis factor).
*LIPID A: causes septic shock involves hypotension (due to
tissue pooling of fluids), disseminated intravascular
coagulation and fever and is often fatal from massive system
failure. This includes lack of effective oxygenation of
sensitive tissues such as the brain. There is no effective
therapy to reverse the toxic activity of lipid A or
peptidoglycan in patients.

* Endotoxins also activate the alternate complement pathway.
* cytokines production results in attraction of
polymorphonuclear cells into affected tissues.
* PG and LPS and certain other cell wall components (e.g.
pneumococcal teichoic acid) are also activators of the
alternate complement cascade
* Endotoxins are also potent polyclonal B cell activators and
adjuvants (for both antibodies and cell mediated immunity);
this plays a role in the development of a suitable chronic
immune response in handling the microbes if they are not
eliminated acutely.
*In a "primary" infection during the acute phase "non-antigen
specific" immunity will be of utmost importance in
eradicating the infection.
* important in chronic infections such as tuberculosis, leprosy,
Lyme disease and syphilis

Basic structure of endotoxin (lipopolysaccharide) from
Gram-negative bacteria

*Immunopathology:
*can occur in acute and chronic infections.
*Over stimulation of cytokine production and complement
activation by endotoxins can cause tissue injury in the
absence of an immune response.
* Continuously generated antigens released from persisting
viable microbes will subsequently elicit humoral antibodies
and cell mediated immunity resulting in chronic
immunopathology.
* Certain poorly degradable antigens (e.g pneumococcal
polysaccharide and group A streptococcal cell walls) can
maintain immunopathology

Bacterial Pathogenesis

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Bacterial Pathogenesis