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Immunity to Infectious Agents Chun-Keung Yu, DVM, PhD Department of Microbiology and Immunology College of Medicine, National Cheng Kung University April 20, 2010 Summary of Chapter 13 Immunity to viruses • Innate immune mechanisms (interferon, NK cells, and macrophages) restrict the early stages of infection and delay spread of virus. • As a viral infection proceeds, the adaptive (specific) immune response unfolds. • Viruses have evolved strategies to evade the immune response. • Responses to viral antigens can cause tissue damage. (Immunopathology) Innate (non-specific) immune response to viral infection • Body surface • Early non-specific or innate immune – Interferon (IFN) • Type I IFNs (IFN α and IFN β) (virus-infected cells) • Type II IFN or IFN γ (activated T and NK cells) – Natural killer (NK) cells – Macrophages ‘Danger’ Signal dsRNA is a signature of viral replication Activation of NF- λB and IFNs 4 Virus-infected cells = resistant status Bcl-2 and caspase cascade eIF-2 Blocks translation of uninfected cells Increase expression of MHC class I and II, and thus antigen presentation Killing signal for CTLs Major antiviral cells in early phrase Plasmcytoid DC2 1.A major IFNα producer after viral infection 2. Toll-like receptor -3 < 2 days after viral infection 1. Cytolysis by perforingranzyme 2. IFN γ: protect uninfected cells and activate macrophages 3. Mediate ADCC IFNγ 1. Phagocytosis of virus and virus-infected cells 2. Kill virus-infected cells 3. Produce antiviral molecules: TNFα, NO, IFNα Adaptive (specific) immune response to viral infection • Cytotoxic T lymphocytes (CTLs) • Helper T (Th) cells • Antiviral antibodies Restrict virus spread in blood stream (between cells and tissues) Neutralization of infectivity Classical and alternative pathways By MAC Via FcγRIII recognization and perforin-dependent killing T cell-mediated antiviral immunity • Antibody response: CD4+ T cells help antibody class switching and affinity maturation • CD8+ CTLs – All cells express MHC class I molecules – Any viral protein can be processed and interacted with MHC class I molecules – MHC class I-restricted CD8+ CTLs destroy virus-infected cells (perforin, granzymes, Fas-FasL) – CD4+ T cell-derived IL-2: CD8+ T cell growth factor CD4+ T cell-derived chemokines: recruit CD8+ T to site of infection – Prevention of re-infection (antibody > CTLs) • Macrophages – CD4+ T cells secrete IFNγ and TNFα to recruit and activate macrophages Adaptive (specific) immune response to viral infection 9 7 5 6 8 IFNγ IFNα and IFNβ Neighboring uninfected cells 1 3 4 2 Protection Killing Lymph nodes and spleen Blood and infected tissues IFNs Activated T cells are absent by the 2nd and 3rd weeks. T cell memory may last for many years Viruses have evolved strategies to evade antiviral responses • Evade recognition by antibody and T cells – Antigenic variation – Amino acid changes (nt sequence changes = mutation) on proteins targeted by antibody and T cells – HIV, FMDV, influenza virus (antigenic drift and shift) • Disrupt interferon system • Encode cytokine homologs (eg. vIL-10, vIL-6, vTNFR) • Encode complement protein homologs • Disrupt chemokine network • Control the expression MHC molecules Antigenic drift = slight antigenic change Antigenic shift = radical antigenic change Mediated cell attachment Antibody to HA are protective Internal antigens are relatively stable Responses to viral antigens can cause tissue damage (1) • Immune complex – Persistent or chronic infections with a large amounts of viral antigen making antibody ineffective (non-neutralizing) – Deposition in kidney or blood vessels (inflammation) • Antibody-dependent enhancement (ADE) of virus infection – Weakly neutralizing antibody – Fc receptor-mediated uptake antibody-virus complexes by macrophages – Dengue virus infection: cross-reactive antibodies from different subtypes; DHF, DSS • CTL response causes tissue damage – LCMV in mice, chronic active hepatitis in humans (are related to immune status) T cell-mediated T cell depletion No death Responses to viral antigens can cause tissue damage (2) • Infection of immunocompetent cells – Death of cell (eg., HIV), ineffective immunity – Transformation leading to neoplasia (Epstein-Bar virus, HTLV-1) • Autoimmunity – Exposure of ‘hidden’ antigens as a result of virus-induced inflammatory response – eg., Theiler’s virus and murine hepatitis virus infection of the CNS; myelin become the targets for antibody and T cells. • Molecular mimicry – ‘self’ protein is recognized by the immune response since it is homologous to a viral protein – Breakdown of immunological tolerance to cryptic self antigens leading to attack on host tissues – eg., Coxsackie B virus-induced cardiomyopathy gp120 Integration of host cell’s genomic DNA Summary of Chapter 14 Immunity to bacteria and fungi • Mechanisms of protection from bacteria can be deduced from their structure and pathogenicity. • Lymphocyte-independent (innate) bacterial recognition pathways have several consequences. • Antibody provides an antigen-specific protective mechanism. (specific) • Ultimately most bacteria are killed by phagocytes. • Infected cells can be killed by CTLs. • Successful pathogens have evolved mechanisms to avoid phagocyte-mediated killing. • The response to bacteria can result in immunological tissue damage. • Fungi can cause life-threatening infections. • Yersinia pestis: killed ¼ of European population in the Middle Ages. • Myocbacterium tuberculosis: infect 1/3 of the world population Immune defenses against pathogenic bacteria are determined by their • Surface chemistry • Mechanism(s) of pathogenicity • Extracellular or intracellular parasite Different immunological mechanisms have evolved to destroy cell wall structure of different groups of bacteria There are four types 7 8. Impede C’ and phagocytosis Targets for Ab 6 5. Compound cell wall extremely resistant to breakdown 3 1 4. Lysis by cationic proteins and complement Killing by phagocytosis 2. Lysosomal enzymes Asterisk (*) are recognized by the innate immune system as a non-specific ‘danger’ signal Downloaded from: StudentConsult (on 30 August 2006 05:13 AM) © 2005 Elsevier Neutralizing antibody is protective Protection requires cellmediated immune responses Antibody and cellmediated responses are required • The first lines of defense do not need antigen recognition: skin, epithelial surfaces, fatty acid, ciliary action in trachea, low pH in stomach and vagina. – Commensals limits pathogen invasion • The second line of define is mediated by recognition of bacterial components. (innate) – Microbial components bearing ‘pathogen-associated molecular pattern’ (PAMPs) (‘danger’ signal) – PAMPs are recog(nized by the ‘pattern recognition molecules’ of the innate immune system • Collectins and ficolins • Toll-like receptors • NOD proteins Pattern recognition molecules • Toll-like receptor (TLR) family – At least ten TLRs: TLR1, 2, 4, 5, 6 and 9 – Express on phagocytes, dendritic cells, epithelial cells with a different combination • Mannose receptor • Scavenger receptors • Complement • C-reactive protein • Mannose-binding lectin • Surfactant protein A in lung LPS is the dominant activator of innate immunity in Gram (-) bacteria Endotoxin shock 1 2 Acute phase response 4. release 3. transfer to II TLR4 TLR4 I III Other bacterial components as immune activators • Cell well components: peptidoglycans and lipoteichoic acids → TLR2, 1, 6 • Lipid components from mycoplasma, mycobacteria, and spirochetes → LBP, CD14 • Mycoplasma lipoproteins → TLR2/6 • Flagellin → TLR5 • DNA (CpG motifs) → TLR9 (express in phagosomes) • Peptidoglycans of G(+) and G(-) → NOD-1 and NOD-2 proteins in cytosol 1. Inflammation 2. Activation of clotting system, fibrin formation = innate Limit bacterial spreading 4 1. Recognition molecules in blood 3 2.Alternative 5. PAMPs 8 6. Recognition receptors on cells i.e., TLRs 7 1 What happen after bacterial recognition? • • • Activation of the alternative pathway of complement – Lytic complex (C5b-9): kill bacteria with outer lipid bilayer – C5a: attracts and activates neutrophils and cause mast cell degranulation (histamine and LTB4) – C3 derivatives: opsonization Proinflammatory cytokines production – TNF, IL-1 (from macrophages): increase adhesive properties – Chemokines: attracts leukocytes – TNF, IL-1, IL-6: induce acute phase responses (complements…) – IL-12, IL-18: stimulate NK cells to release IFN γ to activate macrophages Induction of lymphocyte-mediated response (innate to acquired) – Immature DCs in periphery migrate to draining lymph nodes to prime T cells – Activated macrophages at site of infection act as APC to further activate effector T cells – TLR activation induces a local environment rich in IFN γ, IL-12, and IL-18 which favors TH1 pathway Alternative complement pathway only Most bacteria are killed by phagocytes • A few Gram-negative bacteria are killed by complement • Most bacteria are killed by phagocytes – Neutrophils in blood – Resident macrophages in tissues • Phagocytes are attracted by bacterial components and complement products to site of infection – Cellular composition: pyogenic = acute, rich in neutrophils; granuloma = chronic, rich in macrophages PAMPs LPS : TLR4 Flagellin : TLR5 LP/PG : TLR2/1/6 Pattern recognition molecules Complement components Complement-fixing antibody: IgM > IgG3 > IgG1 Bacterial components Trigger uptake, cytokine secretion, and kill mechanisms Killing pathways of phagocytes • Oxygen dependent – Reduction of oxygen to superoxide anion, formation of free radicals and toxic derivatives – Formation of nitric oxide (inducible NO synthase) • Oxygen independent – – – – Defensins Acidification of phagosomes Lysosome Lactoferrin and Lactoferricin Macrophage killing enhanced on activation by (1) microbial products via TLRs (induce TH1 response) and (2) cytokines (IFNγ) NK cells, NK T cells, and macrophages produce IFNγ. Th1 T cells are the major source of IFNγ. In lymph nodes TLRs Direct cell contact High IL-12 low High IL-10 and TGF β Th2 In site of infection Treg Bacteria-infected cells can be killed by CTLs (viruses, Listeria spp) Cross-presentation MHC class I (ER); See Fig7.11 FasL -Fas (Mtb) MHC class I Other T cell populations can contribute to antibacterial immunity • Non-conventional T cells (cytotoxic activity and secrete IFNγ) • γδ T cells – Epithelial surfaces – Recognize phospholigands • CD1-restricted αβ T cells – Recognize glycolipids – Presented by CD1 (non-polymorphic homologs of MHC class I) on DC Some tissue cells express antimicrobial mechanisms • Secrete defensins by epithelial cells • Infected cells as targets of CTLs • Restrict the growth of intracellular microbial 1. Toxins inhibit chemotaxis 2. Capsule repel attachment 3. Inhibit phagosomelysosome fusion; Inhibit proton pump 4. Catalase neutralize H2O2 8. Resident in cytoplasma 5. Resistant coating 6. LAM blocks IFN γ signal 7. Block antigen presentation Pathogenic bacteria escape the effects of antibody 1.Avoid the effects of antibody 2.Alter antigenic composition (b) (4) Adsorb and deplete local Ab (a) (3) (c) (2) (1) Pathogenic bacteria escape the effects of complement O antigen on LPS shedding Sialic acid Factor H and I Smooth surface of G(-) C5a protease Group A Strept Resist insertion © 2005 Elsevier Response to bacteria can result in immunological tissue damage • • • • Endotoxin shock Schwartzman reaction Koch phenomenon Superantigens induce massive cytokine release Superantigens of G(+) bacteria G(-) bacteria Diffuse intravascular coagulation (DIC) Defective clotting, increase vascular permeability, loss of fluid in tissues, full in blood pressure, circulatory collapse, hemorrhagic necrosis (1) (2) A cytokine-mediated tissue damage in a site of previous inflammation Local inflammation and upregulation of cytokine receptors by IFN γ secreted by NK and NK T cells Systemic cytokine release (TNF) (hemorrhagic rash) Systemic infection Extracellular Intracellular