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1、病毒与宿主相互作用,李怡璇,What is a virus?,A virus is a piece of bad news wrapped in protein.Peter Medawar(1915-87),Nobel prize winner,Viruses(from the Latin virus meaning toxin or poison)体积非常微小，必须用电子显微镜才能看到的非细胞型微生物；结构简单，无完整细胞结构，仅有一种核酸（RNA或DNA）；严格的细胞内寄生性，只能在一定种类的活细胞中增殖；对抗生素不敏感，但对干扰素敏感。,Viruses are far smaller t
2、han their host cells,The Baltimore Classification,Why to study virus-host interactions？,Mechanism:The life cycle of viruses Viral pathogenesis Application:Research Tools Virotherapy,Contents,Part I:Virus-cell InteractionsPart II:Host immune responses to viral infection,Virus-cell Interactions,The se
3、quential steps in viral infectionEntry Primary site replicationSpread within the hostSheddingTransmission,Part I,Schematic diagram to illustrate possible sites of virus entry into the body.,Cycle of infection,Secondary sites,Spread,Entry,Shedding,Shedding,LocalLymphatic Blood(viremia)Neuronal,Primar
4、y sites,Virus-cell Interactions,病毒嗜性（Viral tropism）某一病毒感染宿主的细胞组织特异性；病毒嗜性也决定病毒感染的宿主范围。病毒的感染和复制部位发病或致病部位在病毒大量复制的部位，病损程度并不一定严重；病变严重的部位病毒却不一定大量复制。,Part I,决定病毒嗜性的因素 病毒受体细胞表面的受体，为糖蛋白，糖脂，粘多糖等。不同的病毒采用不同的细胞受体。在某些情况下，病毒进入细胞需要多个受体或共受体的参与。同一病毒的不同病毒株可能吸附不同的受体。并非所有表达病毒受体的细胞均能支持病毒完成增殖。细胞受体在宿主物种间的差异可能限制了病毒的宿主范围。,Mo
5、lecular backbone cartoons of some glycoprotein viral receptors.Cell 1995,82:531-533.,Viral attachment proteints(VAP),A naked virus An enveloped virus,Three different types of virus-cell surface molecule interactions,Models of penetration by animal viruses,Receptor expression is necessary but not suf
6、ficient to explain poliovirus tissue tropism.Journal of virology 1992,66:296-304.,Other determinants of tropism,Activation of viral attachment or fusion proteins by host proteases Cellular transcription factors Temperature sensitivity of virion pH lability of virion Anatomical barriers Host innate a
7、nd acquired immune response,Schematic representation(approximately to scale)of the viral fusion proteins of six different virus families.J Virol.2003,77(16):88018811.,The papillomavirus life cycle is tied to epithelial cell differentiation.,细胞表面受体；各种蛋白质的细胞：有利于病毒吸附、复制、组装和释放；其他物理因素：病毒可在细胞外环境中生存；宿主免疫反应
8、。,决定病毒嗜性的因素（概括）,Virus-cell Interactions,Viral tropismHow do viruses affect cells?,Part I,-大多数病毒感染是无症状的-病毒性疾病是一种“不寻常”的感染后果,分子水平变化 细胞结构改变 细胞表型改变,信号途径 DNA复制 转录 翻译,细胞膜改变 包涵体 细胞骨架改变,细胞死亡 细胞周期抑制 细胞融合 细胞转化 稳定状态感染,Cell molecular responses to viruses,Responses to viral attachment:activate or block signaling
9、cascade mimic the normal ligand for the receptors,The MAPK pathways in vertebrates follow a three-kinase module model for transmitting signals from the cell surface to the nucleus to execute an appropriate biological response.The MAPK/ERK pathway is presented with its key components and the hepatiti
10、s virus proteins known to target the pathways are indicated.Virus Res.2003,92(2):131140.,Cell molecular responses to viruses,Responses to viral attachment:activate or block signaling cascadeViral modulation of host cell transcription,host genes,DownregulationUpregulationUnchange,Virusinfection,Genom
11、ics analysis:an integrated approach,Overview of gene expression in PBMCs from variola-infected macaques.A total of 2,387 elements displayed 3-fold change in mRNA expression.Data from individual elements or genes are represented as a single row,and different time points in the time courses(triangles)
12、are shown as columns.Red and green denote expression levels greater or less,respectively,than baseline values(average of two to four samples taken at days-4 and 0 before inoculation).Proc Natl Acad Sci U S A.2004,19;101(42):1519015195.,Transcription of host RNAP II genes is repressed following HSV-1
13、 infection.(A and B)Nuclear run-on transcription analysis of cellular and viral gene transcription in HeLa cells infected with wild-type virus,KOS1.1.(C)Abundance of RNAP II and GTFs in mock-infected and HSV-1-infected cells.J Virol 1997,71(3):2031-40.J Virol 2001,75(20):9872-84.,细胞mRNA,病毒mRNA,Cell
14、molecular responses to viruses,Responses to viral attachment:activate or block signaling cascadeViral modulation of host cell transcriptionViral modulation of host cell protein synthesis,Virus-induced shutoff of host cell protein synthesis.Murine NIH 3T3cells(lanes 1 to 4)orMadin-Darby bovine kidney
15、 cells(lanes 5 and 6)were mockinfected(U)or infected(I),respectively,with EMCV(lanes 1 and 2),VSV(lanes 3 and 4),or inuenza virus(lanes 5 and 6).Microbiol Mol Biol Rev 2000,64(2):239-80.,细胞蛋白病毒蛋白,病毒抑制宿主细胞蛋白质合成的机制,竞争机制(VSV)大量的病毒 mRNA病毒 mRNA与核糖复合体亲和力高 抑制宿主细胞mRNA从胞核向胞浆转运(Adenovirus)促进宿主细胞mRNA降解(HSV)抑制细
16、胞mRNA翻译的起始和延伸(Poliovirus),Schematic illustration of eukaryotic mRNA translation and major sites of viral regulation.Microbiol Mol Biol Rev 2000,64(2):239-80.,内部核糖体进入位点(IRES,internal ribosome entry site)是mRNA 5端非编码区的一段特殊RNA结构元件，允许核糖体不依赖帽子结构，而是直接与此序列结合，并启动翻译。,Poliovirus genome(+ssRNA),including an IRE
17、S.1988,Viralproteases,Modications of eIF4GI during viral infections.Biology of the Cell 2003,95:141156,蛋白质组学分析,Analysis of virion/cell composition by mass spectrometry.Typical approaches for analyzing virion or cell protein composition by MALDI-TOF(matrix-assisted laser desorption ionizationtime of
18、flight)mass spectrometry and LC-MS/MS(liquid chromatography-linked tandem mass spectrometry).Microbiol Mol Biol Rev 2007,71(2):398-411,http:/,蛋白质组学分析,Visualization of the HIV-1 human protein interaction network.Colored circles represent human proteins and are shown clustering around the HIV-1 protei
19、n they interact with.Human proteins that interact with multiple viral proteins are shown toward the center of the image rather than clustered around a specific HIV-1 protein.AIDS Res Hum Retroviruses.2008,24(12):14971502.,Identification of 1448 human proteins that interact with HIV-1 comprising 2589
20、 unique HIV-1-to-human protein interactions.Preliminary analysis of the extracted data indicates 32%were direct physical interactions(e.g.,binding)and 68%were indirect interactions(e.g.,up-regulation through activation of signaling pathways).AIDS Res Hum Retroviruses.2008,24(12):14971502.,分子水平变化 细胞结
21、构改变 细胞表型改变,信号途径 DNA复制 转录 翻译,细胞膜改变 包涵体 细胞骨架改变,细胞死亡 细胞周期抑制 细胞融合 细胞转化 稳定状态感染,Cell structure changes,病毒诱导的细胞膜结构改变（Virus-induced alterations in cellular membrances）封闭和下调细胞表面的病毒受体 调节 MHC 的表达 病毒蛋白质发挥离子通道的功能,Vpu,Nef and Vpu prevent cell surface expression of CD4 by different mechanisms.The viral glycoprotei
22、n Env(gray)binds to the cellular receptor CD4(green)during transport in the ER.Vpu also binds to CD4 in the ER and targets it for degradation(green fragments)by recruitment to the ubiquitin-proteasome pathway through interactions with b-TrCP and Skp1p.Nef removes preexisting CD4 from the cell surfac
23、e by recruiting CD4 into clathrin-coated pits,and ultimately into degradative lysosomes,through interactions with the AP-2 adaptor complex.Science 1998,280:1880-1884.,The MHC class I antigen presentation pathway.Immunology 2003,110:163-169.,Viral inhibition of the MHC class I antigen presentation pa
24、thway.Immunology 2003,110:163-169.,HCMV US2,3,6,10,11HSV ICP47 Adenovirus E19HHV-7 U21HHV-8 K3,K5HIV-1 Nef,Influenza A Virus M2 protein as proton transporter.M2-TM exists in two conformational ensembles.In the Openout-Closedin conformation the Val-27 gate is open and the His-37 gate is closed wherea
25、s the reverse is true for Closedout-Openin conformation.At high pH out,the Openout-Closedin conformation is favored,because pH out decreases the His-37 residues get protonated and channel is activated at Kact favoring the Closedout-Openin conformation.Release of protons into the viral interior and d
26、eprotonation of His-37 stabilizes the Openout-Closedin conformation and the cycle is repeated until equilibration.PNAS 2009,106(4):1069-74.,Cell structure changes,包涵体（Inclusion body）Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances,usually proteins.They typically represe
27、nt sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins.,Rabies:Negri bodies,HSV,VZV：Cowdry bodies,Cell structure changes,细胞骨架,The main cytoskeleton components participating to host cell/virus interaction;in white,cytoskeleton-perturbating ag
28、ents able to interfere with viral infection,and,in green,the main viral proteins involved in HIVhost cell interaction.Cell Death Differ 2006,13(5):876.,gp-120-induced polarization of T cells.After gp120 binding,CD4+T cells undergo cytoskeleton-driven polarization of CD95 and ezrin and CD95/ezrinmole
29、cular association(see boxed area showing ezrin-CD95/Fas coimmunoprecipitation),resulting in an increased susceptibility to Fas-mediated apoptosis.Cell Death Differ 2006,13(5):876.,分子水平变化 细胞结构改变 细胞表型改变,信号途径 DNA复制 转录 翻译,细胞膜改变 包涵体 细胞骨架改变,细胞死亡 细胞周期抑制 细胞融合 细胞转化 稳定状态感染,Virus-induced cytopathology,病毒增殖性复制不
30、一定摧毁宿主细胞;病毒复制没有完成也可以引起细胞病变效应。病毒诱导的细胞死亡:凋亡（apoptosis）坏死（necrosis）,Virus-induced cell death:apoptosis and necrosis,Cells may die through two pathways,necrosis or apoptosis.Some viral proteins act directly to induce apoptosis while others act indirectly,by neutralizing the effect of a host cell protein
31、 that blocks apoptosis.Some virus proteins can block the apoptosis pathway,leading to prolonged cell life and increasing the yield of progeny virions.Blocking of apoptosis is also a characteristic of some transforming viruses.,Apoptosis signaling pathways.Abbreviations:DD,death domain;FADD,Fas-assoc
32、iated death domain;DED,death effector domain;DISC,death-inducing signaling complex;tBID,truncated Bid;Apaf-1,apoptosis protease-activating factor.Annu Rev Microbiol 2008,62:171192.,Control of Mitochondrial Membrane Permeabilization(MMP)by Viral Proteins.A number of viral polypeptides modulate apopto
33、sis,either by favoring or inhibiting MMP.This control can be exerted directly at mitochondria,or on upstream/downstream steps of the apoptotic cascade.PLoS Pathog 2008,4(5):e1000018.,Some viruses produce proteins that both induce apoptosis and block apoptosis.,Virus-induced cytopathology,Virus-induc
34、ed cell death:apoptosis and necrosis病毒的致畸作用（Viral oncogenesis）,Molecular determinants in the conversion from normal to the malignant cellular phenotype.Hanahan D,Weinberg RA.The hallmarks of cancer.Cell 2000,100:57-70.,Viral oncogenesis,肿瘤病毒:是指在体外可以引起培养的细胞转化，在体内可以诱导肿瘤形成的病毒。,DNA tumor viruses RNA tum
35、or viruses(retroviruses),Representative oncogenic DNA viruses of human,DNA肿瘤病毒编码病毒转化蛋白 病毒复制所必须的蛋白 激活癌基因或抑制抑癌基因致畸作用,The action of the retinoblastoma protein(pRb)and the effect of viral oncoproteins that bind it.,DNA tumor viruses RNA tumor viruses(retroviruses),Oncogenesis mechanism of RNA tumor viru
36、ses,Non-acute transforming retroviruses（非急性转化逆转录病毒）前病毒整合引入插入突变，从而使得细胞抑癌基因失活或者细胞癌基因激活，导致肿瘤发生。,Intergration of retrovirus proviral DNA into a host DNA molecule.,Mechanism of transformion by non-acute transforming retroviruses(blue boxes:provirus;grey boxes:oncogene).Nat Rev Cancer.2003,3(7):477-88.,ci
37、s activation,trans activation,control element disruption,gene-product alteration,Retroviral insertional mutagenesis can occur in humans,as illustrated by acute lymphatic leukemia(ALL)as an unwanted complication of retroviral-mediated gene therapy.N Engl J Med.2004,350(9):913-22.,Molecular Architectu
38、re of the LMO2 Gene and Break Points for Retroviral Insertion or Chromosomal Translocations.N Engl J Med.2004,350(9):913-22.,Acutely transforming retroviruses（急性转化逆转录病毒）病毒携带的病毒癌基因(v-onc)来自宿主细胞的原癌基因(c-onc)病毒癌基因致畸性强多为缺陷病毒，需要辅助病毒(“helper”virus)协助才能完成增殖,Integration of RNA virus genome and host cell geno
39、me,病毒能够独立增殖 癌基因不是病毒增殖所必需的 去除病毒癌基因，病毒失去了致畸能力,缺陷病毒，需要辅助病毒协助才能完成增殖 癌基因与病毒蛋白融合表达 病毒结构基因被破坏,Proto-oncogene and oncogene,Trans-activating transforming retroviruses（反式激活的逆转录病毒）通常编码一个或多个病毒蛋白，它们可以使细胞永生化。人类肿瘤病毒：HTLV-I.,Diagram of putative transforming action of HTLV-1.HTLV-I is transmitted by cell-to-cell con
40、tact of HTLV-I-infected cells.After infection,HTLV-I promotes clonal proliferation of infected cells by Tax and HBZ.However,proliferation of HTLV-I-infected cells is also controlled by CTLs in vivo.During the latency period,the genetic and epigenetic alterations accumulate in the host genomes.In lat
41、e phase,the expression of Tax is inactivated,suggesting that Tax is not always necessary in this stage.On the other hand,HBZ is important in all phases.Int J Hematol 2003,78:312-320.,Virus-induced cytopathology,Virus-induced cell death:apoptosis and necrosisViral oncogenesis 病毒持续感染状态（Viral persisten
42、ce）,Viral persistence,Host is not killed by the virus.The virus is able to evade the immune defenses.,Strategy for persistence,HBV HIV HSV,HPV Non-cytocidal cytocidal silent immune variable active tolerance immune response immune response,Host immune responses to viral infection,Part II,抗病毒免疫（Antivi
43、ral immunity）病毒诱导的免疫病理（Virus-induced immunopathology）病毒诱导的免疫抑制（Virus-induced immunosuppression）,Antiviral immunity,Innate immunity(nonspecific),The 25-oligo A synthetase,The protein kinase,Antiviral immunity,Innate immunity(nonspecific)Acquired immunity(specific)Humoral immunity(antibody)Cellular im
44、munity(cytotoxic T cells,helper T cells),Schematic representation of the effectiveness of the components of the antiviral immune response against different forms of HIV-1.Neutralizing antibodies are efficient in blocking virus particles but poorly effective against cell-associated virus,such as viru
45、s-infected cells.Some CTLs are effective against virus-infected cells but not against free virus particles.Neither antibodies nor CTLs are effective against latently infected cells.Nat Med 2004,10(8):806-810,Host immune responses to viral infection,抗病毒免疫（Antiviral immunity）病毒诱导的免疫病理（Virus-induced im
46、munopathology）病毒诱导的免疫抑制（Virus-induced immunosuppression）,病毒诱导的免疫损伤,A selected list of immune-mediated viral disease of animals and human.Viral pathogenesis and immunity.Second Edition.2007.,What is the evidence that a virus disease is immune-mediated?,Clinical dataPathological examinationExperimenta
47、l animal,Virus-induced immunopathology,Immune mechanism of virus-induced disease,Cell-mediated immunopathologyAntibody-mediated immunopathology病毒诱导的自身免疫病（Virus-initiated autoimmunity）,Virus-initiated autoimmunity,病毒感染可诱发宿主免疫系统的B和T细胞能够特异性识别病毒编码的蛋白质多肽；一些病毒多肽表位与宿主细胞的蛋白质具有同源性；病毒诱导的表位特异性的抗体和T淋巴细胞也能识别宿主细胞
48、的同源蛋白；这种抗宿主免疫反应可以诱导自身免疫病的产生。,Compilation of several diseases reported to be possibly associated with mechanism of molecular mimicry.FASEB J 1998,12(13):1255-65.,Host immune responses to viral infection,抗病毒免疫（Antiviral immunity）病毒诱导的免疫病理（Virus-induced immunopathology）病毒诱导的免疫抑制（Virus-induced immunosup
49、pression）,Selected examples of human and animal viruses that cause immunosuppression.Viral pathogenesis and immunity.Second Edition.2007.,Virus-induced immunosuppression,Mechanism of immunosuppression,病毒感染淋巴细胞、单核细胞和树突细胞；免疫耐受：将病毒作为自体（耐受通常与致死或者是新发病毒感染有关，它是由于病毒特异的T淋巴细胞克隆被清除所导致）；病毒蛋白扰乱免疫反应。,Virus-host interaction:an evolutionary view,Natural selectionDriving force for generation of mutationsLateral gene transferShaping the immune systemViruses and hosts co-evolve,Virus-host interaction was,is,and will be shaping lives of both sides！,Thank you!,microbial musings,
