Immunity to microbes (mechanisms of defense against bacterial infections)

1. Immunity to microbes (mechanisms of defense against bacterialinfections)

2. Goal To understand basic principlesof defense against infections induced by: bacteria - extracellular - intracellular viruses • parasites • protozoa • helmints fungi

3. Important features of defense against infectious agents Mediated by the mechanisms of both innate and adaptive immunity Specialization of the immune system allows optimal response to each type of microbe Establishment, course and outcome of infectiondepend on ability of pathogen to evade or resist immune response Tissue injury and disease areoften result ofimmune response to pathogens

4. Bacteria Unicellular prokaryotes Survive and replicate: - outside cell (extracellular bacteria) - inside cell (intracellular bacteria) Induce disease by: - induction of inflammation - production of toxins

5. Extracellular bacteria Replicate outside cell (in circulation, tissues and lumens) Induceinflammation (often with pus formation) - e.g. staphylococciand streptococci Produce toxins: - exotoxins (diphteria, tetanus...) - endotoxin (LPS)

6. Mechanisms of defense against extracellular bacteria Mechanisms of innate immunity - complement activation by alterative and lectin pathway - phagocytosis (neutrophilsand macrophages) - inflammation (induction of TNF, IL-1, chemokines etc.)

7. Complement activation by alterative and lectin pathway

8. Phagocytosis and killing of microbes Pathogen recognition

9. Phagocytosis and killing of microbes Zipping of membrane around microbe

10. Phagocytosis and killing of microbes Ingestion of microbe

11. Phagocytosis and killing of microbes Fusion of phagosome with lysosome

12. Phagocytosis and killing of microbes Phagocyte activation

13. Phagocytosis and killing of microbes Killing of microbe

14. Inflammation

15. Mechanisms of defense against extracellular bacteria Mechanisms of adaptive immunity Humoral immunity B cells and antibodies - complement activation by clasical pathway (IgG and IgM) - neutralization of toxins (IgG and IgA) - opsonization and phagocytosis (IgG) CD4+helper T cells

16. Mechanisms of defense against extracellular bacteria (B cells)

17. Neutralization of toxins

18. Opsonization andphagocytosis

19. Mechanisms of defense against extracellular bacteria Mechanisms of adaptive immunity Humoral immunity B cells and antibodies - complement activation by clasical pathway(IgG and IgM) - neutralization of toxins (IgG and IgA) - opsonization and phagocytosis (IgG) CD4+helper T cells - B cell help (various citokines) - macrophage activation (IFN-γ) – TH1 - neutrophil activation (IL-17) – TH17 - induction of inflammation (TNF)

20. Naivna CD4+T Naïve CD4+T Macrophage stimulation TH1 IFN- IL-4 IL-5 Eosinophil stimulation TH2 Neutrophil stimulation IL-17A TH17

21. Naivna CD4+T Naïve CD4+T Defence against intracellular pathogens TH1 Defence against helmints TH2 Defence against some extracellular bacteria and fungi TH17

22. Mechanisms of defense against extracellular bacteria Mehanisms of immune evasion - polysaccharide capsule (S. pneumoniae...)

24. Mechanisms of defense against extracellular bacteria Mehanisms of immune evasion - polysaccharide capsule (S. pneumoniae...) - genetic variation of surface antigens (Neisseria sp, E. coli...) - inhibition of complement activation (many bacteria) - production of IgA proteases (Neisseria sp., S. pyogenes...)

25. Mechanisms of defense against extracellular bacteria Injurious effects of immune response - inflammation (SIRS, septic shock) - superantigens (S. aureus, S. pyogenes...)

26. Mechanism of superantigen action T-cell Activation of 5-20% T cells Massive cytokine production Antigen-presentingcell

27. Mechanisms of defense against extracellular bacteria Injurious effects of immune response - inflammation (SIRS, septic shock) - superantigens (S. aureus, S. pyogenes...) - “molecular mimicry” (S. pyogenes and Rheumatic fever)

28. Intracellular bacteria Survive and replicate in cells Enter cells via receptors or phagocytosis Escape from antibody, complement etc. Induce chronic infections Facultative intracellular (e.g. Mycobacterium sp.) Strict intracellular (ChlamydiaandRicketsia)

29. Intracellular bacteria

30. Mechanisms of defense against intracellular bacteria Mechanisms ofinnate immunity - phagocytosis (inefficient unless stimulated) - NK cells (productionof IFN-γand stimulation of macrophages)

31. Stimulation of macrophages by NK cells

32. Mechanisms of defense against intracellular bacteria Mechanisms ofadaptive immunity Cell-mediated immunity CD4+helper T cells(TH1) - B-cell helpto produce opsonizing antibodies (IFN-γ) - macrophage activation (IFN-γ) – TH1 - induction of inflammation (TNF) CD8+ cytotoxic T cells

33. Macrophage activation by TH1 cells

34. Mechanisms ofaquired immunity Cell mediated immunity CD4+helper T-cells(TH1) - Support of B-cellsto produce opsonizing antibodies (IFN-γ) - Macrophage activation (IFN-γ) – TH1 - Induction of inflammation (TNF) CD8+ cytotoxic T-cells Mechanisms of defense against intracellular bacteria - destruction of infected cells (containing bacteria in cytoplasm)

35. Cooperation between CD4+and CD8+ T-cellsin elimination of intracellular bacteria

36. Mechanisms of defense against intracellular bacteria

37. Mechanisms of defense against intracellular bacteria Mehanisms of immune evasion - inhibition of phagolysosome formation (M. tuberculosis...)

38. Mechanism of immune evasion by Mycobacteria

39. Mechanisms of defense against intracellular bacteria Mehanisms of immune evasion - inhibition of phagolysosome formation (M. tuberculosis...) - escape from phagolysosome (L. monocytogenes....) - inhibition of ROS i NO (M. leprae...)

40. Mechanisms of defense against intracellular bacteria Injurious effects of immune response • chronic inflammation (DTH) and granuloma formation • (tuberculosis)

43. Thanks for your attention! Questions?