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Chapter 11: Immunological Responses to Microbes General Features - Microbes must surpass physical and chemical barriers and then deal with innate and adaptive immune systems in order to establish an infection - Intracellular bacteria use the macrophage to grow by preventing fusion of the lysosome with the phagosome (Classic example is Mycobacterium tuberculosis causative agent of TB) - Extracellular bacteria with polysaccharide capsule prevent phagocytosis (remember proteins usually antigenic meaning that only proteins cause a good immune response) - Other extracellular bacteria secrete toxins that cause diarrhea or massive proliferation followed by cell death (apoptosis). Host Defenses to Extracellular Bacteria General features - eliminated by soluble mediators and phagocytosis - Examples of extracellular bacteria 1. Borrelia burgdorferi Lyme’s disease; transmitted by ticks and enter bloodstream 2. Staphylococcus aureus localized skin infections (boils, furuncles); becomes pathogenic when intact skin barriers are broken 3. Neisseria gonorrhea gonorrhea; eliminated by complement mediated osmotic lysis it prevents both direct and opsonin mediated phagocytosis 4. Streptococcus pneumonia bacterial pneumonia Physical and chemical barriers - Physical barriers: intact skin, mucosal surfaces, mucosal secretions have bactericidal and bacteriostatic proteins (e.g. lactoferrin binds iron required for bacteria to grow; lysozyme cleaves bacterial cell wall); mucus layer Phagocytes, phagocytosis, and cytokines - Phagocytosis is the primary mechanism by which extracellular bacteria are eliminated - Opsonins enhance phagocytosis (e.g. C3b, IgG) - Opsonins do not affect the destruction of the organism; this depends on the fusion of the phagosome with the lysosome, and release of bactericidal products reactive oxygen intermediates (via activation of NADPH oxidase), nitric oxide, and reactive nitrogen intermediates - Activated macs secrete cytokines - Production of many bactericidal factors enhanced by the cytokine IFN- & TNF. Complement - opsonin (C3b) - MAC destruction by osmotic lysis Antibodies - activate classical pathway (IgM & IgG IgM better) - opsonins - neutralize toxins CD4+ T cells and cytokines - Type 1 cytokines (IFN- and TNF) enhance killing by phagocytes - T cell derived cytokines required for B-cell activation which leads to isotype switching and differentiation to plasma cells which secrete antibody. Resistance to Immunity: Extracellular Bacteria Streptococcus pneumonia - polysaccharide capsule prevents phagocytosis - B cell activation occurs but mostly IgM produced (Why? Type II T-independent response (Remember: pneumococcal polysaccharide) which isn’t very effective) - Polysaccharide not processed by MHCII (remember: only protein is) CD4s not activated no B cell help no isotype switching - T-independent antigens lack memory so this infection can prove fatal - No IgG produced no opsonization (no activation of innate immunity) Host Defenses to Viruses General features - Epstein-Barr Virus (causative agent of mononucleosis) encodes an IL-10-like molecule that inhibits cytotoxic T cells required to kill virally infected cells (Why? IL-10 inhibits Th1 response since it is a Type 2 cytokine no IL-2 produced no activation of Thp) - Requires either NK cells or cytotoxic T cells - IL-2 (type 1 cytokine) required to activate cytotoxic T cells (CD8) - When viral particles bud from the cell antibodies or phagocytes effective Phagocytes, phagocytosis and cytokines - if virus is found in blood, lymph or interstitial fluid they may be phagocytosed - viruses only found in fluids during the initial infectivity stage or when released from cell - phagocytosis is not a primary mechanism to eliminate viral infections Natural killer cells and osmotic cell lysis - Two ways in which NKs kill virally infected cells: 1. Direct: NK receptor recognizes viral proteins on infected cell surface 2. Indirect: FcgR ADCC = antibody-dependent cellular cytotoxicity (Fc portion Ab bound to virus binds to NK cell) - NK cell perforin osmotic lysis - Perforin does not kill NK cell - NKs most effective during the early phase of infection - NKs have killer inhibitory receptor (KIR) binds to MHCI no killing CD8s kill virally infected cells by binding to MHCI Increased expression of MHCI by the action of IFNturns off NKs CD4+ T cells and cytokines - dendritic cells dectect viral particles in interstitial fluid, blood or lymph, antigen presentation occurs ONLY during the initial infectivity stage or when virus is released - differentiation to Th1 required to secrete IL-2 in order for naïve CD8s to differentiate into CTLs B cells and antibody production - IgG neutralize free virus by binding to receptor for virus so that it can’t bind and also promote its phagocytosis CD8+ T cells and osmotic cell lysis - use perforin to cause osmotic lysis of the virally infected cell Comparison of CTL and NK cell responses to viral infections - lethal hit is the same (both use perforin and death by osmotic lysis) - IL-12 promotes differentiation of type1 cytokine producing cells - IL-12 also gives a proliferative and stimulatory signal to NK cells - NKs can deliver the lethal hit without further differentiation (pCTLs must differentiate to CTL requires antigen contact and IL-2) - IL-2 enhances NK cytotoxicity - NK cells have a broad specificity receptor. CD8s recognize infected cells by MHCI - NK cell is inhibited by MHCI expression on the target cell (mediated by KIR). Increased MHCI expression enhances CTL cytotoxicity Resistance to Immunity: HIV General features - HIV causative agent of AIDS - HIV destroys CD4+ T cells directly or indirectly - Opportunistic infections and malignancies - Destruction of CD4 mediated by normal host defenses that destroy virally infected cells Transmission of HIV - sexual intercourse - exposure to contaminated blood or body fluilds - perinatally - HIV binds to CD4 on T cells, dendritic cells, and macrophages - Binding to coreceptor (CCR5) required for macrophage tropic strains of HIV - T cell tropic strains of HIV use CXCR4 Seroconversion - antibodies dectected in serum - not a useful marker for anti-viral immunity Productive infection of CD4+ T cells - replication in T cells occurs primarily in activated T cells Syncytia formation and cell destruction - CD4 molecules react with viral proteins on the infected cell membrane leading to fusion and functional destruction of the two cells - May contribute to decrease in uninfected CD4+ T cells during HIV infection Disease progression - decline in CD4+ T cell numbers and non-antigen specific immunosuppression Host Defenses to Intracellular Bacteria General features - found in macrophage phagolysosome - cellular immunity is primary effector mechanism (not humoral immunity) - key cells in immunity: cytokine activated macrophages Food borne/oral-fecal intracellular bacteria - food borne intracellular bacteria removed by peristalsis but some bacteria escape by binding to M cells - some bacteria use macrophage as their niche Airborne intracellular bacteria - bacteria that escape mucus enter lung by transcytosis through the epithelial cells or inside macrophages (Trojan horse) - Mycobacterium tuberculosis prevents fusion of phagosome/lysosome and replicate within the phagosome Resistance to Immunity: Intracellular Bacteria Mycobacterium tuberculosis - bacteria reactivated when person becomes immunocompromised - PPD previously infected individuals develop a skin reaction mediated by memory CD4+ T cells (DTH – Mantoux reaction) Host defense - Key cells IFN-, TNF activated macs - IL-12 stimulates IFN- production by NK cells - IFN- enhances the production of ROI, nitric oxide, and RNIs - M. leprae scavenges reactive oxygen species - Granulomas: macrophages surrounded by CD4+ T cells secreting type 1 cytokines particularly IFN- Shigella dysenteriae - escape peristalsis by binding to M cells; escapes into M cell cytoplasm where they replicate and spread laterally to infect adjacent epithelial cells Host Defenses to Fungi General features - mycoses: fungal infections - problem in immunocompromised (opportunistic infections e.g. Candida albicans, Aspergillus) - superficial infections ringworm, athlete’s foot - systemic infections Cryptococcus neoformans - Cryptoccocus neoformans is a common infection in AIDS patients - polysaccharide capsule prevents phagocytosis - eliminated by opsonin-mediated phagocytosis - after sequestration in macs, IFN- required for optimal activation of intracellular killing; patients with low CD4+ T cell counts have impaired killing Resistance to Immunity: Fungi Candida albicans candidiasis - in immunosuppressed hosts, oral infection presents as white plaques (thrush) - vaginal infections manisfest as thick discharge and itching of the vulva - phagocytosis is the main mechanism by which candida is destroyed (better if opsonin mediated) - chronic mucocutaneous candidiasis: hole in T cell repertoire Important: Look at Figure 11.8 on page 231