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VirusandhostcellinteractionandpathogenesisPaulZhouInstitutPasteurofShanghaiGeneralconsiderationofvirusandhostcellinteractionImportance•Akeyunderstandingofvirusreplication•Aninsightintobasiccellularandmolecularbiologymechanisms•Aleadtounderstandingcausesforviralpathogenesis•Aleadtothedefinitionofantiviralstrategies•AleadtothebetterviralvectorsforgenedeliveryLevels•Molecularandcellularlevel•Withinahostorganismspreadfromonecelltoanother•InenvironmenttransmissionamongindividualorganismsOutcomesofviralinfectionofacell•Nonproductiveinfection–noviralreplicationandhostcellsurvivalwithorwithoutviralgenomepersistentasepisomalDNAorintegratedintohostgenome(potentialoncogenesisand/orlatentinfection)•Nonproductiveinfection–noviralreplicationbutnon-survivalofhostcell•Productiveinfectionresultsincelldeath•Productiveinfectionwithoutcelldeath(chronicinfection)CytopathiceffectsofvirusinfectionEffectonhostcellDNAreplicationInhibithostcellDNAsynthesis•ToprovidetheprecursorsforviralDNAsynthesissuchasvacciniaincellularDNAdegradation•ToprovidehostcellstructureandreplicationproteinsforviralDNAsynthesissuchasHSVcandisplacecellularDNAfromnuclearcageandrecruitcellularreplicationproteinstoviralstructure•AsasecondaryeffectofinhibitingcellularproteinsynthesissuchasHSVandadenovirusInducehostcellDNAsynthesis•InducehostcellintoSphasesuchasSV40TantigenandadenovirusE1AandE1BMaintainviralDNA•IntegrateviralDNAintohostcellchromosomessuchasretrovirus•MaintainviralDNAasanextra-chromosomalcircularmoleculesuchasEBV,HHV8,andKSAVinlatentlyinfectedcellsEffectonhostcellRNAtranscriptionandexportInhibitionofcellulartranscriptionandexport•DNAvirusescompeteforpolIIpoleraseandtranscriptionfactorsandinhibitInhibitRNAexporting:AdenovirusE1BandE4andHSVICP27andIE63•RNAvirusesforprecursorsforRNAsynthesis1.InhibithostcellRNAsynthesisVSVMproteinandTFII-DandPVandproteolyticcleavageofTATAbindingTBP2.CapsnatchingofinfluenzaAvirus3.InhibitRNAprocessing:NS1andCPSFToensurehighleveltranscriptionuponviralentry•VirallyencodedRNApolymeraseinvirion•Transcriptionfactorinvirion•AnenhancersequenceToensurehighleveltranscriptionoflaterviralgenes•Transactivators–SV40largeTantigen,adenovirusE1A,PVE2,andHSVICP4•AntranscriptionactivatorforelongationduringRNAsynthesisEffectontranslationalmachinery•Modifyinitiationfactorfunctioninvolvedinrecruitmentofthe40SribosomesubunittomRNAe.g.PV2Aprotease–eIF-4GIandIIandPABP;dephosphorylationofeIF-4Ebyadenovirus,PV,andinfluenzavirus;shutoffGRSF-1byinfluenzavirus•ModifyinitiationfactorfunctioninvolvedinbindingofinitiatortransferRNAtothe40Sribosomesubunite.g.virusinfection,PKRactivationandinactivation,phosphorylationanddephosphorylationofeIF-2α-adenovirusVA1;influenzaNS1andP58IPK;HCVE2andNS5A;VacciniaE3LandK3L;HIVTARTRBPandtat;HSVγ34.5•Modifyelongationfactorfunctione.g.eEF1AandHIVMAandPr55gag•DegradecellularmRNA1.HSV-2UL412.dsRNA–IFN–RNA-dependent2’-5’oligoadenylatesynthetase–2-5A–RNaseL•Unconventionaltranslationalstrategies1.Leakyscanninge.g.SV40VP2andVP32.Ribosomeshuntinge.g.interveningregionofanmRNAisbypassedwithoutscanningofribosomesadenoviruslatemRNAs3.Translationalframeshiftinge.g.retrovirus,coronavirus,arterivirus;-1pol4.Suppresstranslationalterminatione.g.polORF5.PosttranslationalRNAeditinge.g.RNAspecificadenosinedeaminasesA-I,IthenreadasGincodonHostcellresponsestoviralinfectionHostresponsetovirusatthecellularlevel•IFNproduction–homologousandheterologousviruses•Apoptosis–untimelyearlydestructionofinfectedcellsmayreducevirusyields•RestrictionfactorsInnateimmuneresponse(dendriticcells)•TLRs–typeIIFNproduction,inflammatorycytokinesanddendriticmaturation,TLR-3andWNV•RNAhelicases–dsRNAproducedduringvirusreplicationandleadsttypeIIFNproductionTLR7and9pathwaysleadtoIFNsandinflammatorycytokinesbyplasmacytoidDCsTLR3pathwaysleadtoIFNsandinflammatorycytokinesCircumventIFNresponsesbyvirusesOutcomesofvirusinfectionofahostRoutesofvirusentryVirusspreadinahostLocalizedversussystemicinfection•Routeofinfection(contact,inhalation,arthropodvectorbite,needle•Celltropism(envelopedversusnon-envelopedviruses)•ApicalversusbasolateralreleaseofvirusinpolarizedepithelialmucosalcellsHematogenousspread•Primaryreplicationinprimarysite•Regionallymphnodes•Efferentlymphatics•Thoracicduct•Systemiccirculation(blood-brainbarrier)•Secondarysites•Insidenerve(poliovirusandHSV)•PrimaryversussecondaryviremiasStagesofpathogenesisofflavivirusinfectionThepathogenesisofmousepoxvirusThemagnitudeanddurationofviremia–thedynamicrelationshipbetweenvirusandhost•ReplicationattheprimaryandsecondarysitesandcirculatingbloodcellssuchasHIVinCD4Tcellsprovideacontinuingsourceofvirusinputintothecirculation•MacrophagesintheRES,serumantibodyandcomplementactinconcerttofacilitateviralclearance(thesizeandnetchargeofvirusparticles,otherpathogen)•Replicatedinmacrophages(HSV,CMV,togavirus,flavivirus,poxvirus,lentiviruses,coronaviruses,arenaviruses,reovirus,piconavirus,rhabdoviruses,myxo-andparamyxoviruses)-circumventantiviraldefenseofmacrophages:HLAdown-regulationandinhibitionofantiviralmoleculeproductionsuchas