Mechanisms of Bacterial Pathogenesis

Transcription

1 Mechanisms of Bacterial Pathogenesis Pin Ling ( 凌斌 ), Ph.D. Department of Microbiology & Immunology, NCKU ext 5632 lingpin@mail.ncku.edu.tw References: 1. Chapter 19 in Medical Microbiology (Murray, P. R. et al; 5 th edition) 2. 醫用微生物學 ( 商惠芳審閱, 6th 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: 1. Transient colonization 2. Permanent colonization 3. 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 1. A diverse microbial flora => Human body Area: the skin and mucous membranes Time: shortly after birth until death Number: bacteria =>10 13 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.

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 Germ-free Animals Regular Counterparts Lifespan Twice One Cause of death Anatomic & Physiological Changes Intestinal Atonia 1. Alimentary lamina propria underdeveloped 2. No Ab 3. Intestinal epithelial cell renewal rate down half Infection

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. w/ normal flora 10 6 pathogenic microbes GI infection 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 1. Local Environment (ph, temperature, redox potential, O2, H2O, and nutrient levels ). 2. Diet 3. Age 4. Health condition (immune activity ) 5. 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 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.

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 1. Transmissibility 2. Adherence to host cells 3. Invasion of host cells and tissue 4. 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

20 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

21 Mechanisms of acquiring bacterial virulence genes

22 Bacterial Virulence Mechanisms

23 Adhesins Bacterial virulence factors 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 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

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 Mode of action Back 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 The A-B toxins-ii Back

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. 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. 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