1. Mechanisms of Bacterial Pathogenesis
Pin Ling (凌 斌), Ph.D.
Department of Microbiology & Immunology, NCKU
ext 5632
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)

2. Outline Normal Flora (Commensal Microbes) Introduction
Significance of the Normal Flora
Distribution of the Normal Flora
Bacterial Pathogenesis
Introduction
Host Susceptibility
Pathogenic Mechanisms
Virulence Factors

3. Normal Flora and Pathogenesis
Outcomes of exposure to a microorganism:
Transient colonization
Permanent colonization
Disease
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.

4. Introduction of Normal Flora
A diverse microbial flora =>
Human body Area: the skin and mucous membranes
Time: shortly after birth until death
Number: 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)
Viruses and parasites => NOT normal microbial flora
Most investigators consider that they are not commensals and do not aid the host.

5. 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.

6. Germ-free Animals vs Counterparts
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

7. 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
10 pathogenic microbes
GI infection
w/ reduced flora after
Streptomycin treatment

8. Normal Flora competing with Invading Pathogens
Adopted from Samuel Baron “Medical Microbiology”

9. Normal flora may act as opportunistic pathogens
Especially in hosts rendered susceptible by:
1. Immuno-suppression (AIDS & SCID)
2. Radiation therapy & Chemotherapy
3. Perforated mucous membranes
4. Rheumatic heart disease…etc.

10. Sites of human body that the normal flora
microbes colonize
Respiratory tract and head
outer ear, eye, mouth, oropharynx, nasopharynx
Sterile sites: sinuses, middle ear, brain, lower respiratory tract (trachea, bronchiole, lung)
Gastrointestinal tract
esophagus, stomach, small intestine, large intestine
Genitourinary system
anterior urethra, vagina
Sterile sites: bladder, cervix, uterus
Skin

11. Distribution of Normal Flora in Human Body
Adopted from Samuel Baron “Medical Microbiology”

12. Factors Influencing Normal Flora
Local Environment (pH, temperature, redox potential, O2, H2O, and nutrient levels…).
Diet
Age
Health condition (immune activity…)
Antibiotics,…..etc

13. Outline Normal Flora (Commensal Microbes) Introduction
Significance of the Normal Flora
Distribution of the Normal Flora
Bacterial Pathogenesis
Introduction
Host Susceptibility
Pathogenic Mechanisms
Virulence Factors

14. Introduction of Bacterial Pathogenesis
Infection: growth and multiplication of a microbe in or on the body with or without the production of disease.
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.

15. 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.

16. 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.

17. Transmission of infection
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.
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
Many bacteria are transmitted on hands

18. Entry into the human body
The most frequent portals of entry- Mucus
- Skin
Routes:
Ingestion, Inhalation, Trauma, Needlestick, Catheters, Arthropod bite, Sexual transmission
: infection
: shedding

19. Characteristics of Pathogenic Bacteria
Transmissibility
Adherence to host cells
3. Invasion of host cells and tissue
Evasion of the host immune system
Toxigenicity
A bacterium may cause diseases by
Destroying tissue (invasiveness)
Producing toxins (toxigenicity)
Stimulating overwhelming host immune responses

20. Pathological Mechanisms of Bacterial Infections
Bacteria-mediated Pathogenesis
Host-mediated Pathogenesis
Bacterial virulence factors
=> bacterial factors causing diseases
Adopted from Samuel Baron “Medical Microbiology”

21. Mechanisms of acquiring bacterial
virulence genes

22. Bacterial Virulence Mechanisms

23. Bacterial virulence factors
Adhesins
Pili (fimbriae)
Nonfimbrial adhesins
Invasion of host cells
Tissue damage
Growth byproducts
Tissue-degrading enzymes
Immunopathogenesis
Toxins
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

24. Adhesion
Back
1. Adherence of bacterium to epithelial or endothelial cells 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, is a special bacterial adaptation that facilitates colonization on the surgical appliances (e.g., artificial valves or indwelling catheters) and dental plaque. It can protect the bacteria from host defenses and antibiotics.

25. Bacteria may invade via the M cells
M (Microfold) cells
Back

26. Endotoxin (LPS)-mediated toxicity
Lipid A of lipopolysaccharide is responsible for endotoxin activity
Pathogenesis of sepsis (septicemia)

27. Endotoxin-mediated toxicity
Fever,
Leukopenia followed by leukocytosis,
Activation of complement, thrombocytopenia,
Disseminated intravasacular coagulation,
Decreased peripheral circulation and perfusion to major organs (multiple organ system failure),
Shock and death.
Peptidoglycan, teichoic and lipoteichoic acids of gram-positive bacteria stimulate pyrogenic acute phase responses and produce endotoxin-like toxicity
Back

28. 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
Back

29. The A-B toxins
A chain has the inhibitory activity against some vital function
B chain binds to a receptor and promotes entry of the A chain
Back
Mode of action
Inhibition of protein synthesis
Hypersecretion
Inhibition of neurotransmitter release
In many cases the toxin gene is encoded on a plasmid or a lysogenic phage

30. Back
The A-B toxins-II

31. Microbial defenses against host immunologic clearance
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

32. Mechanisms for escaping phagocytic clearance and intracellular survival

33. Mechanisms for escaping phagocytic clearance and intracellular survival

34. Mechanisms for escaping phagocytic clearance and intracellular survival

35. Regulation of bacterial virulence factors
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.

36. SUMMARY-I 1. 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

37. SUMMARY-II 4. 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.

38. Figure 19-3 The mode of action of dimeric A-B exotoxins
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 :56 AM)
© 2005 Elsevier

39. Figure 19-3 The mode of action of dimeric A-B exotoxins
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 :56 AM)
© 2005 Elsevier