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Lecture 19 Host Defense Against Infection

Lecture 19 Host Defense Against Infection. Innate immunity Adaptive Immunity. Response to Initial Infection . Stages of Response to Infection. Course of Typical Acute Infection. Innate Host Defense Mechanisms. Anatomic Factors Mechanical Factors Biochemical Factors. Skin.

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Lecture 19 Host Defense Against Infection

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  1. Lecture 19Host Defense Against Infection Innate immunity Adaptive Immunity

  2. Response to Initial Infection

  3. Stages of Response to Infection

  4. Course of Typical Acute Infection

  5. Innate Host Defense Mechanisms • Anatomic Factors • Mechanical Factors • Biochemical Factors

  6. Skin • Stratified and cornified epithelium provides a mechanical barrier • Indigenous microbiota competes with pathogens • Acid pH inhibits growth of disease producing bacteria • Bactericidal long chain fatty acids in sebaceous gland secretions

  7. Respiratory Tract • Upper Respiratory Tract • Nasal hairs induce turbulence • Mucous secretions trap particles • Mucous stream to the base of tongue where material is swallowed • Nasal secretions contain antimicrobial substances • Upper respiratory tract contains large resident flora • Lower Respiratory Tract • Particles trapped on mucous membranes of bronchi and bronchioles • Beating action of cilia causes mucociliary stream to flow up into the pharynx where it is swallowed • 90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoli • Alveoli • Alveolar macrophage rapidly phagocytize small particles

  8. Alimentary Tract • General defense mechanisms • Mucous secretions • Integrity of of mucosal epithelium • Peristaltic motions of the gut propel contents downward • Secretory antibody and phagocytic cells • Stomach • Generally sterile due to low pH • Small Intestine • Upper portion contains few bacteria • As distal end of ilieum is reached flora increases • Colon • Enormous numbers of microorganisms • 50-60% of fecal dry weight is bacteria

  9. Genitourinary Tract • Male • No bacteria above urethrovesicular junction • Frequent flushing action of urine • Bactericidal substances from prostatic fluid • pH of urine • Bladder mucosal cells may be phagocytic • Urinary sIgA • Female (Vagina) • Large microbial population (lactobacilli) • Microorganisms produce low pH due to breakdown of glycogen produced by mucosal cells

  10. Eye • Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynx • Tears contain a high concentration of lysozyme (effective against gram positive microorganisms

  11. Innate Immune Recognition • All multicellular organisms are able to recognize and eliminate pathogens • Despite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs) • Host cells do not share PAMPs with pathogens • PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

  12. Three Functional Classes of PRRs/PRMs • Endocytic receptors • Macrophage mannose receptor • Macrophage scavenger receptor (SR) • Integrin CD11b:CD18 • Secreted proteins • Mannose-binding protein/lectin • Pulmonary surfactant proteins A and D • C-reactive protein (CRP) • Signaling receptors • Toll receptor family

  13. Endogenous Signals Induced by PAMPs • Mediate inflammatory cytokines • Interleukin-1 (IL-1) • IL-6 • Tumor necrosis factor (TNF-a) • Type 1 interferon (INF-I) • Major effector cytokines • Chemokines • Antigen-presenting cells recognize PAMPs • Same APC processes pathogens into specific pathogen-derived antigens and presents them with MHC encoded receptors to T-cells • T-cell responds only when presented with both signals • Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2)

  14. Antimicrobial Peptides/Defensins • Four hundred peptides described to date • Defensins (3- 5-kD, four families in eukaryotes) • a-defensins (neutrophils and intestinal Paneth cells) • b-defensins (epithelial cells) • Insect defensins • Plant defensins • Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane permeability. • May also play a role in inflammation and wound repair

  15. Complement System • Three pathways now known • Classical • Alternative • Lectin or MBL pathway (binding to mannose-containing carbohydrates) • Host cells have complement regulatory proteins on their surface that protect them from spontaneous activation of C3 molecules

  16. Inflammatory Mediators in Innate Immunity • Cytokines secreted by phagocytes in response to infection include: • IL-1 • activates vascular endothelium and lymphocytes • Increases adhesiveness of leukocytes • IL-6 • Induces B-cell terminal maturation into Ig-producing plasma cells • IL-8 • Induces expression of b2 integrin adhesion molecules on neutrophils, leading to neutrophil migration to infection site • IL-12 • Activates NK cells and induces Th1-cell differentiation • IL-18 • TNF-a • Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissues

  17. Other Mediators and Molecules • Phagocytes • Toxic oxygen radicals • Peroxides • Nitric oxide (NO) • Lipid mediators of inflammation • Prostaglandins • LTB4 • Platelet activating factor • Complement component C5a • Stimulates mast cells to release histamine, serotonin and LTB4 • IL-1, IL-6 and TNF-a • Induce acute-phase response in liver • Induce fever • IL-1 and IL-18 signaling pathways activate NF-kB, important in innate immunity

  18. Immune Cells and Innate Immunity • Phagocytes • Neutrophils • Moncyte/macrophage • Eosinophils (to a lesser extent) • NK cells (large granular lymphocytes) • Antibody-dependent cell-mediated cytotoxicity (ADCC) • Have two major functions • Lysis of target cells • Production of cytokines (IFN-g and TNF-a) • Act against intracellular pathogens • Herpesviruses • Leishmania • Listeria monocytogenes • Act against protozoa • Toxoplasma • Trypanasoma

  19. Immune Cells and Innate Immunity (cont’d) • g/d T cells • Two types of T cell receptors • One composed of a and b chains (basic T cell antigen receptor) • One composed of g and d chains (minor population of T cells) • Two groups of g/d T cells • One group found in lymphoid tissues • One group located in paracellular space between epithelial cells • Recognizes unprocessed target antigen in absence of APC help • B-1 cells (minor fraction of B cells, do not require T-cell help) • Mast cells • Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glands • Capable of phagocytosis • Process and present antigen using MHC class I or II receptors • LPS can directly induce release of mast cell mediators • Complement (C3a and C5a) induce mast cells to release mediators • Chemotaxis, complement activation, inflammation • TNF-a secreted by mast cells results in neutrophil influx into infected site

  20. Summary of Innate Immunity • External and mechanical barriers • Receptors for pathogen motifs • Soluble antimicrobial proteins • Pattern of cytokines produced influences adaptive response

  21. Adaptive Immunity and Infection

  22. Protective Role of Antibodies Against Pathogens • Toxin neutralization • Opsonization/enhancement of phagocytosis • Sensitization for killing by NK cells • Sensitization of mast cells • Activation of complement system

  23. Toxin Neutralization

  24. Diseases caused by bacterial toxins

  25. Preventing Bacterial Adherence

  26. Virus-blocking Antibodies

  27. Activation of the Complement Cascade • Cell Activation (anaphylatoxins) • Activate inflammatory cells • Induce smooth muscle contraction and blood vessel permeability • Cytolysis ("membrane attack complexes“) • Loss of cell membrane integrity • Opsonization • Complement receptors on phagocytic cells • Renders cells vulnerable to phagocytosis

  28. Fc Receptors

  29. Opsonization and Immune Adherence • C3B (C4B) • Facilitates adherence of bacteria, viruses and neutrophils to monocytes and macrophages • Facilitates ingestion of certain bacteria by neutrophils and monocytes • Facilitates ingestion by activated macrophages • Augments mediated phagocytosis and IgG-mediated cell cytotoxicity (ADCC) • Antibody • antibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherence

  30. Chemotaxis capillary blood vessel phagocyte endothelium basement membrane Site of inflammation, tissue damage and immune reactions PAVEMENTING C5a DIAPEDESIS CHEMOTAXIS

  31. Phagocytosis

  32. Bactericidal Agents in Phagocytic Cells

  33. Natural Killer Cells and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

  34. Inflammation The four cardinal signs of inflammation (Cornelius Celsus, 30 BC to AD 38): rubor et tumor cum calore et dolore redness and swelling with heat and pain • Increased blood supply to the infected area • Increased capillary permeability • Migration of leukocytes into tissues (Chemotaxis)

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