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Host Defense Lecture 13 Virology W3310/4310 Spring 2012 1 Host defenses • Intrinsic: Physical and chemical -‐ Skin, mucous, tears, low pH, surface cleansing • Innate immune system: First line of immune defense • AdapIve immune system: Tailored to pathogen 2 3 4 Innate immune response • FuncIons conInually in host without prior exposure to virus • AcIvated within minutes to hours aMer infecIon • Only immune defense available for the first few days aMer viral infecIon • Cytokines, senInel cells (dendriIc cells, macrophages), complement, NK cells • Can inform adapIve response when infecIon reaches dangerous threshold 5 How does the innate system recognize microbes and not self? • 1980: Nusslein-‐Volhard and Wieschaus idenIfy gene involved in establishing dorsal-‐ventral axis in Drosophila embryos. Called Toll gene. Nobel Prize, 1995 (“Das war ja toll!”) • 1996: Toll found to have a role in immunity of fly to fungal infecIons • 1997: Toll-‐like receptors idenIfied in mammals 6 TLRs • Type I transmembrane proteins, pacern-‐recogniIon receptors that recognize pathogen-‐associated molecular pacerns (PAMPs) • • Conserved from plants, insects to humans 13 members in humans, mice 7 8 Toll/IL-‐1 receptor (TIR) domain TLR3-‐ECD 9 10 RIG-‐I like helicases 11 12 13 Interferons • 1957: Issacs & Lindenmann found chicken cells exposed to killed influenza virus produce substance that “interfered” with infecIon of other cells • IFNα/β first cytokines to appear aMer infecIon, IFNγ later • Virus-‐infected cells produce IFNα/β • Uninfected senInel cells produce IFNα/β in response to products released from cells (e.g. viral nucleic acid) 14 IFN-‐λ (type III) mainly produced by epithelial cells 15 Interferons • ProducIon of IFNα/β is rapid: within hours of infecIon, declines by 10 h • Many IFNα genes are differenIally expressed aMer infecIon • TranscripIon of IFNβ gene is sImulated only for a short period 16 Interferons • • IFNs induce an anIviral state • • Mechanisms of most ISGs are not known IFN binding to IFN receptors leads to synthesis of over 1000 cell proteins (encoded by ISGs, IFN sImulated genes) ConstellaIons of ISGs probably effecIve for different viruses in different cells 17 18 IFN-‐induced proteins • Pkr -‐ dsRNA-‐acIvated protein kinase -‐ • • acIvated by dsRNA, phosphorylates eIF2α, translaIon inhibited Can inhibit many viruses eIF2α-‐P can trigger autophagy 19 Interferon-‐induced proteins RNase L, 2’-‐5’-‐oligo(A) synthetase 20 Mx proteins • First discovered in mice: Mx1 protein localizes in nucleus, blocks influenza virus cap-‐snatching by inhibiIng polymerase subunit PB2 • BUT influenza virus does not circulate among wild mice; 25% of mouse populaIon lacks mx1 gene without consequences • Two related human genes, mxA, mxB • MxA protein blocks replicaIon of influenza virus, VSV, measles virus, human parainfluenza virus 3, some bunyaviruses 21 Nitric oxide synthase • • Induced by IFNγ • Accounts for much of anIviral acIvity of NK cells Produces nitric oxide, which has anIviral effects 22 Pml (promyelocyEc) proteins • Present in nucleoplasm and in nuclear bodies (Pml bodies, ND10 bodies, PODs -‐ Pml oncogenic domains) • • Bind foreign DNA • Pml bodies disrupted during many virus infecIons Exert anIviral effects by transcripIonal repression and nucleosome remodeling 23 UbiquiEn-‐proteasome pathway components • ISG15, a ubiquiIn-‐like protein that is conjugated to many cell proteins (e.g. involved in RNA splicing, transcripIon, stress responses, translaIon) leading to their degradaIon • • UbiquiIn ligases • Proteasome inhibitors block anI-‐HBV acIon of IFN Increased protein degradaIon may contribute to anIviral response 24 Tetherin, CD137 25 Other ISGs • ISG56 -‐ most strongly IFN induced gene -‐ binds a subunit of eIF3, blocking iniIaIon of protein synthesis • miRNAs -‐ IFNβ treatment of hepatoma cells induces numerous miRNAs, 8 of which inhibit HCV replicaIon • IFNβ treatment reduces expression of liver-‐specific miR-‐122, which is essenIal for HCV replicaIon 26 SenEnel cells • DendriIc cells & macrophages: senInels in peripheral compartments (e.g. skin, mucosal surfaces) • DendriIc cells: first described as Langerhans cells by Paul Langerhans (late 19th century) • Called dendriIc cells in 1973 by Steinman & Cohn TWiV 157: Becer innate than never 27 DCs • Immature dendriIc cells: found in periphery, around body caviIes, under mucosal surfaces. Carry TLRs, RLHs, cytokine receptors • Mature: home to lymph nodes; present internalized proteins on MHC class II to lymphocytes; link innate & adapIve responses • DendriIc cells directly inhibit viral replicaIon at onset of infecIon by producing cytokines such as IFN 28 29 DCs as Trojan horses • HIV-‐1 binds DC-‐SIGN (dendriIc cell specific, Icam-‐3 grabbing nonintegrin), carried into the lymph node where it can infect CD4+ T cells • VEE, dengue replicate in DCs, migrate to lymph nodes to spread infecIon. Vaccine strategy with acenuated viruses? • InfecIon of DCs may have other consequences, e.g. destrucIon, interference with maturaIon, migraIon, maturaIon of T cells 30 The complement cascade • IdenIfied in 1890 as a heat-‐labile factor in serum that lyses bacteria in the presence of anIbody (complemented anIbody) • Major defense and clearance system that bridges the innate and adapIve defense systems • CollecIon of soluble serum and membrane proteins, can recognize invaders by novel pacern-‐recogniIon, and engage anIbodies against the pathogen • Works early and late in infecIon 31 Four funcEons of complement • Cytolysis -‐ make holes in infected cells if they have bound anIbody or have unusual proteins on their surface • AcIvaIon of inflamma8on -‐ cytokines • Opsoniza8on -‐ coat virus parIcles to facilitate uptake by macrophages • Solubiliza8on of immune complexes -‐ break up anIbody-‐anIgen complexes that can damage organs 32 33 Inflammatory response • During the earliest stages of infecIon, cells produce cytokines as intrinsic defenses are acIvated • Tnf-‐α, a cytokine of early warning, causes inflamma8on • Redness; pain; heat; swelling, the four classic signs of inflammaIon (rubor, dolor, calor, tumor, originally recorded by the Roman encyclopedist Celsus in the first century AD) • Result from increased blood flow, increased capillary permeability, influx of phagocyIc cells, Issue damage 34 35 IniIally funcIon locally in anIviral defense In larger quanIIes, enter circulaIon, have global effects (sleepiness, lethargy, muscle pain, no appeIte, nausea) 36 InflammaEon usually sEmulates potent immune responses • Cytopathic viruses cause inflammaIon because they promote cell and Issue damage -‐ • Ac8vate the innate response Consequently cytopathic viral genomes encode proteins that modulate this immune response -‐ Adenoviruses, herpesviruses, poxviruses 37 Some viruses do not acEvate the adapEve immune response well • • Do not s)mulate the inflammatory response Typically non-‐cytopathic viruses -‐ Cells are not damaged -‐ Cells do not die of infecIon -‐ Low or ineffecIve innate immune response • Non-‐cytopathic viruses have drama)cally different interac)ons with the host immune system -‐ Arenaviruses, paramyxoviruses -‐ Cause persistent infecIons: infecIons are rarely or inefficiently cleared 38 The lesson • The classic inflammatory response (heat, swelling, redness, pain) reflects the communicaIon of innate and adapIve immune defense -‐ • no inflammatory response, ineffec8ve adap8ve response One reason for using inflammaIon-‐sImulaIng adjuvants for noninfecIous vaccines 39 40 The innate defense system • • Cytokines, pacern detectors, NK cells, complement • If early defenses are breached by viruses, the innate system signals the adapIve defense system to kick in Takes care of most infecIons before we know what’s going on 41 AdapEve responses are essenEal for eradica'ng infected cells and virus parEcles (clearing the infecEon) 42 Effectors of the adapEve response TWiV 161: Concerto in B 43 Neutralizing anEbodies • EssenIal defense against many virus infecIons • Neutralize virus parIcles in the blood, prevent virus spread • IgA at mucosal surfaces (secretory anIbody) blocks entry into the host • Some neutralizing anIbodies are important for recovery from infecIon (picornavirus, togavirus, flavivirus, parvovirus) 44 Passive anEbody protects against poliovirus infecEon 45 hcp://www.virology.ws/2009/05/28/influenza-‐microneutralizaIon-‐assay/ 46 47 Cell mediated immunity • • • • EssenIal for clearing most viral infecIons Th1 response CTL and target cells form an immunological synapse Lysis of target cell by two mechanisms -‐ Transfer of cytoplasmic granules containing perforin and granzymes -‐ Apoptosis 48 AnEbody vs cellular immunity in protecEng against monkeypox virus infecEon 49 For some infecEons, CTL response is more important than the anEbody response How is an effecEve combinaEon of immune defenses produced? Begins in lymph 8ssues where sen8nels tell naive B and T cells nature of invader 50 This decision is made in part by special T helper cells (Th cells) • Th cells make direct contact in the lymph nodes with the senInel dendriIc and macrophage cells that patrol the Issues • InformaIon exchanged (processed pepIdes and cytokines) causes differenIaIon of these naive Th cells -‐ they become Th1 or Th2 cells 51 Th1 or Th2? • Th1 cells secrete cytokines that turn on killer T cells -‐ • Th2 cells secrete cytokines that acIvate B cells -‐ • Most viral infec8ons are cleared by this response (cell-‐ mediated immunity) Good for bacterial and worm infec8ons; not a good response for most viral infec8ons How is the balance determined? -‐ By mix of cytokines produced by sen8nels 52 AdapEve responses also provide memory • If the host is subsequently infected by the same virus, the response will be rapid and specific -‐ • Innate responses don’t have memory Memory: the basis for vaccinaEon 53 54 55
