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Anti-Inflammatory Responses

Anti-Inflammatory Responses. Complement regulatory proteins: e.g. C1 inhibitor, C4 binding protein, Factor H, Factor I, complement receptor CR1, decay accelerating factor. Acute phase proteins e.g. protease inhibitors, ceruloplasmin. PGE 2 , TGF , Prostaglandins IL-10 sIL-1R.

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Anti-Inflammatory Responses

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  1. Anti-Inflammatory Responses • Complement regulatory proteins: e.g. C1 inhibitor, C4 binding protein, Factor H, Factor I, complement receptor CR1, decay accelerating factor. • Acute phase proteins e.g. protease inhibitors, ceruloplasmin. • PGE2, TGF, Prostaglandins • IL-10 • sIL-1R

  2. Immunopathology • Virus-bacterium synergistic pathology • Sepsis and Endotoxemia • Molecular mimicry • Superantigens

  3. Virus-Bacterium Synergy • Enhancement of inflammatory response by bacterial growth, IFN, complement. • Increased tissue damage by bacterial toxins (cytolysin, LPS) • Amplification of macrophage reactivity by cytokines, LPS,

  4. Sepsis and Endotoxemia • Proinflammatory cytokines:TNF, IFN, IL-1, IL-6, IL-8, IFN, IFN • C5a • Neutropenia Soluble cytokine receptors (TNF-R, IL-1R)

  5. Molecular Mimicry • Chlamydia - heart • Campylobacter - Guillan-Barre’ syndrome

  6. Superantigens • S. aureus enterotoxins causing food poisoning, vomiting & diarrhea (SEA, SEB). •  Lymphocyte proliferation •  Cytokine production • Toxic shock syndrome.

  7. Camouflage Encapsulation Antigenic mimicry Antigenic masking Antigenic shift Latency Intracellular replication Subversion Production of anti-Ig proteases Destruction of phagocyte Inhibition of chemotaxis Inhibition of phagocytosis Inhibition of phagolysosome fusion Resistance to lysosomal enzymes Superantigens Immune Evasion

  8. Mechanisms of Immune Evasion I: Camouflage • Capsule formation • S aureus protein A • Sialic acid • LPS O protein • S aureus coagulase • M bacterium granuloma formation

  9. Mechanisms of Immune Evasion III: Anti-Phagocytosis • Inhibit opsonization (S aureus protein A) • Inhibit chemotaxis • Kill phagocyte (S aureus streptolysin) • Inhibit phagocytosis (S pneumoniae capsule, S pyogenes M protein) • Inhibit lysosomal fusion (M. tuberculosis) • Escape lysosome and grow in cytoplasm (Mycobacteria, Salmonella, S. aureus) • Block activation by IFN (Mycobacteria) • Viral envelope glycoproteins • LPS

  10. Mechanisms of Immune Evasion II: Proteases • Inhibit opsonization (N gonorrhoeae IgA protease) • Inhibit chemotaxis • Kill phagocyte (S aureus streptolysin) • Inhibit phagocytosis (S pneumoniae capsule, S pyogenes M protein) • Inhibit lysosomal fusion (M. tuberculosis) • Escape lysosome and grow in cytoplasm (Mycobacteria, Salmonella, S. aureus) • Block activation by IFN (Mycobacteria) • Viral envelope glycoproteins • LPS

  11. Viral Mechanisms of Immune Evasion I • Humoral Response • Latency e.g. HSV, retroviruses • Syncytia formation e.g. HSV, VZV, HIV • Antigenic variation e.g. HIV • Blocking antigen e.g. HBV e Ag • Complement decay e.g. HSV

  12. Viral Mechanisms of Immune Evasion II. • Interferon • HBV blocks transcription of IFN • EBV synthesizes BRC1, an analogue of IL-10. • Adenovirus RNA - double stranded duplex blocks interferon antiviral action; early protein binds cl I heavy chain preventing upregulated expression

  13. Viral Mechanisms of Immune Evasion III • Immune Cell Function • CTL cytolysis e.g. HSV • TH depletion e.g. HIV • Immunosuppression e.g. measles, EBV

  14. Viral Mechanisms of Immune Evasion IV. • Antigen Presentation • Inhibition of Cl I MHC expression e.g. Adenovirus, CMV • Inactivating peptides e.g. HBV • Inhibition of Inflammation • Blocking of inflammatory cytokines e.g. Poxviruses, adenovirus.

  15. Infection and Pathogenesis Colonization (Benign or asymptomatic)Infection   Disease (Pathogenesis)  Clinical or Subclinical

  16. Requisites for Successful Growth • Attachment • Nutrition • Survival from host defence • Transmission

  17. Virulence Factors • Factors which promote infection and which contribute to disease • Studied with mutants • Are multifactorial • Consist of: • Factors promoting colonization and invasion • Factors which are pathogenic

  18. Bacterial Virulence Factors I: Colonization • Adherence: Capsules, Pili, adhesins • Penetration: e.g. invasins • Host gene modification.

  19. Capsules • Present in some gram negative and positive bacteria. • May be composed of protein or polysaccharide layers. • Is poorly antigenic and anti-phagocytic • Can act as a barrier to toxic hydrophobic molecules such as detergents. • Can promote adherence to other bacteria or cell surfaces

  20. Pili (Fimbriae) • Composed of subunits of pilin. • Promote adherence to other bacteria or host. • Synonyms: adhesins, lectins, evasins, aggressins. • Fragile, often replaced.

  21. Bacterial Pathogenesis • Toxic byproducts of bacterial growthe.g. acids, gas, proteases • Toxins • Endotoxins e.g. LPS • Exotoxins • Immunopathogenesis e.g. Chlamydia,treponemes (syphilis), Borrelia (Lyme disease)

  22. Endotoxins: Lipopolysaccharide • Fever • Leukopenia, followed by leukocytosis • Complement activation • Thrombocytopenia • Coagulation • Decreased blood circulation • Shock • Death

  23. Exotoxins • AB. e.g. Shigella dysenteriae, C. tetani, V. cholerae. • Cell Membrane Disruption. e.g. C. perfringens • Superantigens. e.g. S. aureus

  24. Exotoxins I: AB (i)

  25. Exotoxins I:AB (ii)

  26. Exotoxins I: AB (iii)

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