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; 5th edition) 2. 醫用微生物學 (王聖予 等編譯, 4th edition)

Outline Bacterial Pathogenesis Introduction Host Susceptibility Pathogenic Mechanisms Virulence Factors

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 the mechanism of infection and to the mechanism by which disease develops.

Host Susceptibility Susceptibility to bacterial infections => Host Defenses vs Bacterial Virulence 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 Host defenses can be comprised by destructing barriers or defective immune response. e.x. 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.

Entry into the human body The most frequent portals of entry- Mucus - Skin Routes: Ingestion, inhalation, trauma, needles, catheters, arthropod bite, sexual transmission : infection : shedding

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

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

Bacterial Virulence Mechanisms

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

Adhesion Back Adherence of bacterium to epithelial or endothelial cells allow them to colonize the tissue. Common adhesins: pili (fimbriae), slime, lipoteichoic acid, surface proteins or lectins. 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.

The bacteria may invade via the M cells M (Microfold) cells Back

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

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

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 orC Back

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

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

Mechanisms for escaping phagocytic clearance and intracellular survival

Mechanisms for escaping phagocytic clearance and intracellular survival

Mechanisms for escaping phagocytic clearance and intracellular survival

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.

SUMMARY 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

Mechanisms of acquiring bacterial virulence genes