Transcript
BLS 1st & 2ND YR 2008/09
BACTERIAL PATHOGENESIS
LECTURE 2
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Why we do not get ill?
(i) the entire invading population is killed by phagocytic cells,
such as neutrophils, or circulating bacteriocidal compounds,
such as complement
(ii) the density of bacteria traversing the integument is
collectively too low to condition the tissue to allow their
population to grow or
(iii) the mutations or phase shifts required to get across the
mucosa or survive in the blood do not occur.
It is complex and strong stochastic
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Introduction
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, a term which refers to the degree of pathogenicity of the
microbe.
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.
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The relationship between a host and a pathogen is dynamic, since
each modifies the activities and functions of the other.
The outcome of such a relationship depends on:
the virulence of the pathogen and
the relative degree of resistance or susceptibility of the host,
mainly due to the effectiveness of the host defense mechanisms.
Introduction
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Animals and microbes
Normal flora (beneficial or ignored): GI track, skin, upper respiratory track
Virulent bacteria (actively cause disease): pathogenic islands
Opportunistic bacteria (when host with underline problem): Pseudomonas aeruginosa: cystic fibrosis/ burn
TB, Kaposi’s sarcoma (herpesvirus): AIDS
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Mechanisms of Bacterial Pathogenicity
1. Invasiveness: the ability to invade tissues.
encompasses mechanisms for
colonization (adherence and initial multiplication),
production of extracellular substances which facilitate
invasion (invasins) and
ability to bypass or overcome host defense
mechanisms.
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2. Toxigenesis: ability to produce toxins.
Bacteria may produce two types of toxins:
i. exotoxins and
ii. endotoxins.
Mechanisms of Bacterial Pathogenicity
Exotoxins are released from bacterial cells and may act at
tissue sites removed from the site of bacterial growth.
Endotoxins are cell-associated substance. (classic sense,
endotoxin refers to the lipopolysaccharide component of the
outer membrane of Gram-negative bacteria).
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Endotoxins may be 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).
Hence, bacterial toxins, both soluble and cell-associated,
may be transported by blood and lymph and cause cytotoxic
effects at tissue sites
Some bacterial toxins may also act at the site of colonization
and play a role in invasion.
Mechanisms of Bacterial Pathogenicity
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Animals and microbes
Normal flora (beneficial or ignored): GI track, skin, upper respiratory track
Virulent bacteria (actively cause disease): pathogenic islands
Opportunistic bacteria (when host with underline problem): Pseudomonas aeruginosa: cystic fibrosis/ burn
TB, Kaposi’s sarcoma (herpesvirus): AIDS
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Koch’s postulates:
1. suspected pathogen must be present
2. pathogen must be isolated and grown in pure culture
3. cultured pathogen must cause the disease
4. Same pathogen must be re-isolated from the subject
Big person in microbiology
Robert Koch,1843-1910, Germany
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Bacterial pathogenesis
Infection/entry
Virulence factors
Pathogenesis
Escape of immune surveillance
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Infection/entry
Ingestion (fecal-oral)
Inhalation (respiratory)
Trauma (e.g burn)
Arthropod bite (zoonoses:
mosquito, flea, tick,
Tsetse fly)
Sexual transmission
Iatrogenic (needle stick,
blood transfusion)
Maternal-neonatal
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Bacteria, virus, fungi
Ingestion: Salmonella, Shigella, Vibrio, Clostridium etc..
Inhalation: Mycobacterium, Mycoplasma, Chlamydia etc..
Trauma: Clostridium tetani
Arthropod bite: Rickettsia, Yersinia pestis, etc.
Sexual transmission: Neisseria gonorrboeae, HIV, chlamydia, etc
Needle stick: Staphylococcus, HIV, HBV
Maternal-neonatal: HIV, HBV, Neisseria, etc.
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Modes of infectious disease transmission
Contact transmissionDirect contact (person-to-person): syphilis, gonorrhear, herpesIndirect contact (fomites): enterovirus infection, measlesDroplet (less than 1 meter): whooping cough, strep throat
Vehicle transmissionAirborne: influenza, tuberculoses, chickenpoxWater-borne (fecal-oral infection): cholera, diarrheaFood-borne: hepatitis, food poisoning, typhoid fever
Vector transmissionBiological vectors: malaria, plaque, yellow fever Mechanical vectors: E. coli diarrhea, salmonellosis
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Extracellular versus Intracellular Parasitism
Extracellular parasites
destroyed when phagocytosed.
damaging tissues as they remain outside cells.
inducing the production of opsonizing antibodies, they
usually produce acute diseases of relatively short duration.
Intracellular parasites
can multiply within phagocytes.
frequently cause chronic disease.
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The environment in a cell
Cytosol: pH=7
Phagosome: pH=6
Phagolysosome: pH=5
Adapted from: http://bio.winona.msus.edu/bates/Bio241/images/figure-04-13b.jpg
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Barrier systems
Host cell
membrane
Taken up by
phagocyte
and resist killing
Inhibitory
molecule
Mycobacterium
Production
Of antibody
Degrade
antibody
IgA protease Streptococcus
Antimicrobial
cell-mediated
response
Activate T cells
non-specifically
and
Productively
Superantigen Staphylococcus
Antimicrobial
immune
response
Vary presenting
microbial
antigen
Switch on
production of
different
antigens
Borrelia
Genetic
recombination
Streptococcus
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Virulence factors
Factors enhancing the ability of bacteria to cause disease
Example: Pseudomonas aeruginosa
Adhesins: attachment
Alginate production: mucoid layer
Exotoxin A: inhibits host protein synthesis
Exoenzyme S: interferes with phagocytic killing
Elastolytic activity: degrades elastin
Phospholipase C: damages tissue
Pyocyanin: damages tissue by ROS
Antibiotic resistance: complicates therapy
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Pathogenic action of bacteria
Tissue destruction: flesh-eating bacteria:
Clostridium perfrigens
Obstruction: Cytic fibrosis
Toxins: bacterial components that directly
harm tissue or trigger disease symptoms
Endotoxin: lipopolysaccharides
Exotoxin: A-B toxins
Immunopathogenesis
Excess immune responses
Autoimmunity
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2. Endotoxins: heat stable
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Endotoxin: lipopolysaccharide
IL-1
TNF
Pseudomonas aeruginosa
Fever
Disseminated intravascular coagulation
Septic shock
death
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Superantigens
Polyclonal T cell activation
Aberrant cytokines,
cell death
Specific T cell activation
Anti-microbes immunity
Antigen
/MHC-1
Secreted proteins
(exotoxins) that exhibit
highly potent lymphocyte-
transforming (mitogenic)
activity directed towards T
lymphocytes.
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Known and suspected association of superantigens with
animal diseases
Autoimmune diseases
Lyme disease
Multiple sclerosis
Acute diseases
Food poisoning:
Staph infections
Streptococal
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EVASION STRATEGIES (1)
Defence Microbial strategy Mechanism Example
Wash-out Bind to cell Adhesins Neisseria
Inhibit ciliary
activity
Ciliotoxic/
Ciliostatic
molecule
Bordetella
Streptococcus
Ingestion
and
killing by
phagocyte
Disrupt
Chemotaxis
cytotoxic
Leucocidins Staphylococcus
Inhibit
phagocytosis
Capsule Streptococcus
Inhibit lysosomal
fusion
Inhibitory
molecule
Mycobacterium
Multiply Unknown Listeria
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EVASION STRATEGIES (2)
Defence Microbial strategy Mechanism Example
Restrict Fe-
Lactoferrin
Transferrin
Compete Siderophore Mycobacterium
Escherichia
Activate
complement
Interfere with
alternative pathway
Fully sialylated
surface
Neisseria
Inactivate Elastase Pseudomonas
Antigen projects
beyond surface
Activation occurs
at the wrong site
Gram-negatives
Interfere with
complement-
mediated
phagocytosis
C3b receptor
competition,
microbe and
phagocyte
Streptococcus
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