Immunity to microbes (mechanisms of defense against bacterial infections)

Goal To understand basic principles of defense against infections induced by: bacteria - extracellular - intracellular viruses parasites protozoa helmints fungi

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 infection depend on ability of pathogen to evade or resist immune response Tissue injury and disease are often result of immune response to pathogens

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

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

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

Complement activation by alterative and lectin pathway

Phagocytosis and killing of microbes Pathogen recognition

Phagocytosis and killing of microbes Zipping of membrane around microbe

Phagocytosis and killing of microbes Ingestion of microbe

Phagocytosis and killing of microbes Fusion of phagosome with lysosome

Phagocytosis and killing of microbes Phagocyte activation

Phagocytosis and killing of microbes

Inflammation

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

Mechanisms of defense against extracellular bacteria (B cells)

Neutralization of toxins

Opsonization and phagocytosis

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)

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

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

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

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...)

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

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

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)

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 (Chlamydia and Ricketsia)

Intracellular bacteria

intracellular bacteria Mechanisms of defense against intracellular bacteria Mechanisms of innate immunity - phagocytosis (inefficient unless stimulated) - NK cells (production of IFN-γ and stimulation of macrophages)

Stimulation of macrophages by NK cells

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

Macrophage activation by TH1 cells

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

Cooperation between CD4+ and CD8+ T-cells in elimination of intracellular bacteria

Mechanisms of defense against intracellular bacteria

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

Mechanism of immune evasion by Mycobacteria

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...)

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

Thanks for your attention! Questions?