mechanisms of bacterial pathogenesis pin ling ( 凌 斌 ), ph.d. department of microbiology &...
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Mechanisms of Bacterial Pathogenesis
• Pin Ling ( 凌 斌 ), Ph.D. Department of Microbiology & Immunology, NCKUext [email protected]
• References: 1. Chapter 19 in Medical Microbiology (Murray, P. R. et al; 5th edition) 2. 醫用微生物學 ( 王聖予 等編譯 , 4th edition)
Normal Flora (Commensal
Microbes) • Introduction• Significance of
the Normal Flora• Distribution of
the Normal Flora
Bacterial
Pathogenesis
• Introduction
• Host Susceptibility
• Pathogenic
Mechanisms
• Virulence Factors
Outline
Colonization vs. Infection
Colonization: establishment of a site of reproduction of microbes on a person without necessarily resulting in tissue invasion or damage.
Infection: growth and multiplication of a microbe in or on the body of the host with or without the production of disease.
Outcomes of exposure to a microorganism:1. Transient colonization2. Permanent colonization 3. Disease
Normal Flora and Pathogenesis
Introduction of Normal Flora
1. A diverse microbial flora => Human body Area: the skin and mucous membranes Time: shortly after birth until deathNumber: 1014 bacteria =>1013 host cells
2. Normal flora may:a. Aid the host b. Harm the host (in sometimes)c. Exist as commensals (no effect to the host)
3. Viruses and parasites => NOT normal microbial flora Most investigators consider that they are not commensals and do not aid the host.
Significance of Normal Flora-I
1. The normal flora influences the anatomy, physiology,
susceptibility to pathogens, and morbidity of the host.
2. The effect of the normal flora on the host was not well understood until germ-free animals became available. Cesarean Section => Germ-free animals => Isolators
w/o detectable pathogens (viruses, bacteria & others)
3. Two interesting observations:a. the germ-free animals lived almost twice as long as
their conventionally maintained counterparts.b. the major causes of death were different in the
two groups.
Germ-free Animals Regular Counterparts
Lifespan Twice One
Cause of death
Intestinal Atonia Infection
Anatomic & Physiological Changes
1. Alimentary lamina propria under-developed
2. No Ab
3. Intestinal epithelial cell renewal rate down half
Germ-free Animals vs Counterparts
Significance of Normal Flora-II
Normal flora may aid the host in several ways:• Aid in digestion of food• Help the development of mucosa immunity • Protect the host from colonization with
pathogenic microbes.
106 pathogenic microbes GI infection
w/ normal flora
GI infectionw/ reduced flora afterStreptomycin treatment
10 pathogenic microbes
Normal flora may act as opportunistic pathogens
Especially in hosts rendered susceptible by:1. Immuno-suppression (AIDS & SCID)2. Radiation therapy & Chemotherapy3. Perforated mucous membranes4. Rheumatic heart disease…etc.
Respiratory tract and head outer ear, eye, mouth, oropharynx, nasopharynx Sterile sites: sinuses, middle ear, brain, lower respirator
y tract (trachea, bronchiole, lung)
Gastrointestinal tract esophagus, stomach, small intestine, large intestine
Genitourinary system anterior urethra, vagina Sterile sites: bladder, cervix, uterus
Skin
Sites of human body that the normal flora microbes colonize
1. Local Environment (pH, temperature, redox potential, O2, H2O, and nutrient levels…).
2. Diet
3. Age
4. Health condition (immune activity…)
5. Antibiotics,…..etc
Factors Influencing Normal Flora
Normal Flora (Commensal
Microbes) • Introduction• Significance of
the Normal Flora• Distribution of
the Normal Flora
Bacterial
Pathogenesis
• Introduction
• Host Susceptibility
• Pathogenic
Mechanisms
• Virulence Factors
Outline
Introduction of Bacterial Pathogenesis
1. Infection: growth and multiplication of a microbe in or on the body with or without the production of disease.
2. The capacity of a bacterium to cause disease reflects its relative “Pathogenicity.”
3. Virulence is the measure of the pathogenicity of a microorganism.
4. Pathogenesis refers both to (1) the mechanism of infection and to (2) the mechanism by which disease develops.
Host Susceptibility
1. Susceptibility to bacterial infections => Host Defenses vs Bacterial Virulence
2. Host Defenses: - Barriers (skin & mucus) – the first line - Innate Immunity (complement, macrophages & cytokines) – the early stage - Adaptive Immunity (Ag-specific B & Tcells)–the later stage
3. Host defenses can be comprised by destructing barriers or defective immune response. e.g. Cystic Fibrosis => poor ciliary function => NOT clear mucus efficiently from the respiratory tract => Pseudomonas aeruginosa => serious respiratory distress.
Strict pathogens
are more virulent and
can cause diseases in a
normal person.
Opportunistic
pathogens are typically
members of normal flora
and cause diseases when
they are introduced into
unprotected sites; usually
occur in people with
underlying conditions.
Transmission of infection
Carrier: a person or animal with asymptomatic infection that can be transmitted to another person or animal.
The clinical symptoms of diseases produced by microbes often promote transmission of the agents.
Zoonosis: infectious diseases transmitted between animals and men.
Hospital- (nosocomial) vs. community-acquired infections
By producing asymptomatic infection or mild disease, rather than death of the host, microorganisms that normally live in people enhance the possibility of transmission from one person to another.
Many bacteria are transmitted on hands
Entry into the human body
: infection : shedding
The most frequent portals of entry- Mucus - Skin
Routes:Ingestion, Inhalation, Trauma, Needlestick, Catheters, Arthropod bite, Sexual transmission
1. Transmissibility2. Adherence to host cells3. Invasion of host cells and tissue4. Evasion of the host immune system 5. Toxigenicity
A bacterium may cause diseases by
1. Destroying tissue (invasiveness)
2. Producing toxins (toxigenicity)
3. Stimulating overwhelming host immune responses
Characteristics of Pathogenic Bacteria
Pathological Mechanisms of Bacterial Infections
1. Bacteria-mediated Pathogenesis
2. Host-mediated Pathogenesis
3. Bacterial virulence factors
=> bacterial factors causing diseases
Adopted from Samuel Baron “Medical Microbiology”
Bacterial virulence factors
Adhesins Pili (fimbriae) Nonfimbrial adhesins
Invasion of host cells Tissue damage
Growth byproducts Tissue-degrading enzymes
ImmunopathogenesisToxins
Exotoxins (cytolytic enzymes and A-B toxins); enterotoxins; superantigens; endotoxin and other cell wall components
Antiphagocytic factors
Intracellular survival
Antigenic heterogeneity Antigenic variation Phase variation
Iron acquisition Siderophores Receptors for iron-containing molecules
Resistance to antibiotics
Adhesion
1. Adherence of bacterium to epithelial or endothelial c
ells allow them to colonize the tissue.
2. Common adhesins: pili (fimbriae), slime, lipoteichoic
acid, surface proteins or lectins.
3. Biofilm, formed on a surface by the bacteria that are
bound together within a sticky web of polysaccharide, i
s a special bacterial adaptation that facilitates colonizat
ion on the surgical appliances (e.g., artificial valves or i
ndwelling catheters) and dental plaque. It can protect t
he bacteria from host defenses and antibiotics.
Back
Lipid A of lipopolysaccharide is responsible for endotoxin activity
Pathogenesis of sepsis (septicemia)
Endotoxin (LPS)-mediated toxicity
1. Fever, 2. Leukopenia followed by leukocytosis,3. Activation of complement, thrombocytopenia, 4. Disseminated intravasacular coagulation, 5. Decreased peripheral circulation and perfusion to
major organs (multiple organ system failure), 6. Shock and death.
Peptidoglycan, teichoic and lipoteichoic acids of gram-positive bacteria stimulate pyrogenic acute phase responses and produce endotoxin-like toxicity
Back
Endotoxin-mediated toxicity
Back
Superantigen-mediated toxicity
1. Bind to TCR and activate T cells w/o Ag
2. Autoimmune-like responses
3. S. aureus =>Toxic shock syndrome toxin
S. pyogenes=> Erythrogenic toxin A or C
The A-B toxins
Mode of action
Inhibition of protein synthesis
Hypersecretion
Inhibition of neurotransmitter release
A chain has the inhibitory activity against some vital function
B chain binds to a receptor and promotes entry of the A chain
In many cases the toxin gene is encoded on a plasmid or a lysogenic phage
Back
Encapsulation (Inhibition of phagocytosis and serum
bactericidal effect)
Antigenic mimicry
Antigenic masking
Antigenic or phase variation
Intracellular multiplication
Escape phagosome
Inhibition of phagolysosome fusion
Resistance to lysosomal enzymes
Production of anti-immunoglobulin protease
Inhibition of chemotaxis
Destruction of phagocytes
Microbial defenses against host immunologic clearance
Environmental factors often control the expression of the virulence genes.
Common factors: temperature, iron availability, osmolarity, growth phase, pH, specific ions, specific nutrient factors, bacterial cell-density, interaction with host cells.
Regulation of bacterial virulence factors
SUMMARY-I1. Host Defenses:
- Barriers (skin & mucus) – first line- Innate Immune Responses (complement, macrophages
& cytokines) – the early stage- Adaptive Immune Responses (Ag-specific B & T
cells) – the later stage
2. Susceptibility to bacterial infections depends on the balance between host defenses and bacterial virulence.
3. Pathogenic mechanisms of bacterial infections include • Bacteria-mediated Pathogenesis• Host-mediated Pathogenesis
SUMMARY-II4. Normal flora may aid the host in several
ways:• Aid in digestion of food• Help the development of mucosa immunity • Protect the host from colonization with
pathogenic microbes.
Figure 19-3 The mode of action of dimeric A-B exotoxins. The bacterial A-B toxins often consist of a two-chain molecule. The B chain promotes entry of the bacteria into cells, and the A chain has inhibitory activity against some vital function. ACH, Acetylcholine; cAMP, cyclic adenosine monophosphate. (Redrawn From Mims C et al:
Medical microbiology, London, 1993, Mosby-Wolfe.)
Downloaded from: StudentConsult (on 10 November 2005 09:56 AM)
© 2005 Elsevier
Figure 19-3 The mode of action of dimeric A-B exotoxins. The bacterial A-B toxins often consist of a two-chain molecule. The B chain promotes entry of the bacteria into cells, and the A chain has inhibitory activity against some vital function. ACH, Acetylcholine; cAMP, cyclic adenosine monophosphate. (Redrawn From Mims C et al:
Medical microbiology, London, 1993, Mosby-Wolfe.)
Downloaded from: StudentConsult (on 10 November 2005 09:56 AM)
© 2005 Elsevier