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Pathogenesis<<Part1(clickonthislink)精选课件CellTransformationbyVirusesTransformationisachangeinthemorphological,biochemical,orgrowthparametersofacell.Transformationmayormaynotresultincellsabletoproducetumoursinexperimentalanimals,whichisproperlyknownasneoplastictransformation.Therefore,transformedcellsdonotautomaticallyresultinthedevelopmentof'cancer'.Carcinogenesis(ormoreproperly,oncogenesis)isacomplex,multi-stepprocessinwhichcellulartransformationmaybeonlythefirst,althoughessential,stepalongtheway.精选课件CellTransformationbyVirusesTransformedcellshaveanalteredphenotype,whichisdisplayedasone(ormore)ofthefollowingcharacteristics:LossofanchoragedependenceLossofcontactinhibitionColonyformationinsemi-solidmediaDecreasedrequirementsforgrowthfactors精选课件CellTransformationbyVirusesCelltransformationisasingle-hitprocess,i.e.asinglevirustransformsasinglecell(c.f.oncogenesis,i.e.theformationoftumours,whichisamulti-stepprocess).Allorpartofthevirusgenomepersistsinthetransformedcell&isusually(butnotalways)integratedintothehostcellchromatin.Transformationisusuallyaccompaniedbycontinuedexpressionofalimitedrepertoireofvirusgenes,orrarelybyproductiveinfection.Virusgenomesfoundintransformedcellsarefrequentlyreplication-defective&containsubstantialdeletions.Transformationismediatedbyproteinsencodedbyoncogenes.Cell-transformingvirusesmayhaveRNAorDNAgenomes,butallhaveatleastaDNAstageintheirreplicationcycle,i.e.theonlyRNAvirusesdirectlycapableofcelltransformationaretheretroviruses.精选课件Oncogenes精选课件OncogenesCertainretrovirusescarryhomologuesofc-oncsderivedoriginallyfromthecellulargenes&knownasv-oncs.Incontrast,theoncogenesofcell-transformingDNAvirusesareuniquetothevirusgenome-therearenohomologoussequencespresentinnormalcells.Genesinvolvedintheformationoftumourscanbegroupedbytheirbiochemicalfunctions:Oncogenes&proto-oncogenes:oncogenesaremutatedformsofproto-oncogenes,cellulargeneswhosenormalfunctionsistopromotethenormalgrowth&divisionofcells.Tumoursuppressorgenes:geneswhichnormallyfunctiontoinhibitthecellcycle&celldivision.DNArepairgenes:geneswhichensureeachstrandofgeneticinformationisaccuratelycopiedduringcelldivisionofthecellcycle.Mutationsinthesegenesleadtoanincreaseinthefrequencyofothermutations,e.g.inconditionssuchasataxia-telangiectasia&xerodermapigmentosum.精选课件Oncogenes精选课件CellTransformationbyRetrovirusesNotallretrovirusesarecapableoftransformingcells,forexample,lentivirusessuchasHIVdonottransformcells,althoughtheyarecytopathic.Theretroviruseswhichcantransformcellsfallintothreegroups:transducing,cis-activating&trans-activating.Ifoncogenesarepresentinallcells,whydoestransformationoccurasaresultofvirusinfection?Thereasonisthatoncogenesmaybecomeactivatedinoneoftwoways,eitherbysubtlechangestothenormalstructureofthegene,orbyinterruptionofthenormalcontrolofexpression.精选课件CellTransformationbyRetrovirusesThetransforminggenesoftheacutelytransformingretroviruses(v-oncs)arederivedfrom&arehighlyhomologoustoc-oncs&arebelievedtohavebeentransducedbyviruses.Mostv-oncspossessslightalterationsfromtheirc-oncprogenitors-manycontainminorsequencealterationswhichalterthestructure&thefunctionoftheoncoproteinproduced,otherscontainshortdeletionsofpartofthegene.Mostoncoproteinsfromreplication-defective,acutelytransformingretrovirusesarefusionproteins,containingadditionalsequencesderivedfromvirusgenes,mostcommonlyvirusgagsequencesattheaminoterminusoftheprotein.Theseadditionalsequencesmayalterthefunctionorthecellularlocalizationoftheprotein&theseabnormalattributesresultintransformation.精选课件CellTransformationbyRetrovirusesChronictransformingretrovirusgenomesdonotcontainoncogenes-theyactivatec-oncsbyamechanismknownasinsertionalactivation.Aproviruswhichintegratesintothehostcellgenomeclosetoac-oncsequencemayindirectlyactivatetheexpressionofthegeneinawayanalogoustothatinwhichv-oncshavebeenactivatedbytransduction.Thiscanoccuriftheprovirusisintegratedupstreamofthec-oncgene,whichmightbeexpressedviaaread-throughtranscriptofthevirusgenomeplusdownstreamsequences.Insertionalactivationcanalsooccurwhenaprovirusintegratesdownstreamofac-oncsequenceorupstreambutinaninvertedorientation.Activationresultsfromenhancerelementsintheviruspromoter&canoccureveniftheprovirusintegratesseveralkilobasesawayfromthec-oncgene.Examples:inchickens,insertionofavianleukosisvirus(ALV)activatesthemycgene;inmice,mousemammarytumourvirus(MMTV)insertionactivatestheintgene.精选课件InsertionalActivation精选课件Trans-ActivatingRetrovirusesHumanT-cellleukaemiavirus(HTLV)&relatedanimalvirusesencodeatranscriptionalactivatorproteininthevirustaxgene.ThetaxproteinactsintranstostimulatetranscriptionfromthevirusLTR.Itisbelievedthattheproteinalsoactivatestranscriptionofmanycellulargenesbyinteractingwithtranscriptionfactors.However,HTLVoncogenesis,i.e.theformationofaleukaemictumour,hasalatentperiodofsome20-30years.Therefore,celltransformation(whichcanbemimickedinvitro)&tumourformation(whichcannot)arenotone&thesame-additionaleventsarerequiredforthedevelopmentofleukaemia.ItisthoughtthatchromosomalabnormalitieswhichmayoccurinthepopulationofHTLV-transformedcellsarealsorequiredtoproduceamalignanttumour,althoughthisisnotcompletelyunderstood.精选课件CellTransformationbyDNAVirusesIncontrasttotheoncogenesofretroviruses,thetransforminggenesofDNAtumourviruseshavenocellularcounterparts.SeveralfamiliesofDNAvirusesarecapableoftransformingcells.Ingeneralterms,thefunctionsoftheironcoproteinsaremuchlessdiversethanthoseencodedbyretroviruses.TheyaremostlynuclearproteinsinvolvedinthecontrolofDNAreplicationwhichdirectlyaffectthecellcycle.Theyachievetheireffectsbyinteractingwithcellularproteinswhichnormallyappeartohaveanegativeregulatoryroleincellproliferation.Twoofthemostimportantcellularproteinsinvolvedareknownasp53&Rb.精选课件p53p53formscomplexeswithSV40T-antigen&otherDNAvirusoncoproteins,includingthoseofadenoviruses&papillomaviruses.Thegeneencodingp53ismutatedoralteredinthemajorityoftumours,implyingthatlossofthenormalgeneproductisassociatedwiththeemergenceofmalignantlytransformedcells.p53playsacentralroleincontrollingthecellcycle.Itisbelievedtobeatumoursuppressoror'anti-oncogene'&hasbeencalled'theguardianofthegenome'.p53isatranscriptionfactorwhichactivatestheexpressionofcertaincellulargenes,causingthecellcycletoarrestattheG1phase.SincethesevirusesrequireongoingcellularDNAreplicationfortheirownpropagation,thisexplainswhytheirtransformingproteinstargetp53.精选课件TheCellCycle精选课件RbRbwasdiscoveredwhenitwasnoticedthatthegenewhichencodesthisproteinisalwaysdamagedordeletedinatumouroftheopticnerveknownasretinoblastoma.Therefore,thenormalfunctionofthisgeneisalsothoughttobethatofatumoursuppressor.TheRbproteinformscomplexeswithatranscriptionfactorcalledE2F.Thisfactorisrequiredforthetranscriptionofadenovirusgenes,butE2FisalsoinvolvedinthetranscriptionofcellulargeneswhichdrivequiescentcellsintoSphase.TheformationofinactiveE2F-Rbcomplexesthushasthesameoveralleffectastheactionofp53-arrestofthecellcycleatG1.ReleaseofE2FbyreplacementofE2F-RbcomplexeswithE1A-Rb,T-antigen-RBorE7-RBcomplexesthereforestimulatescellular&virusDNAreplication.精选课件SV40T-AntigenSV40T-antigenisoneoftheknownvirusproteinswhichbindsp53.InfectionofcellsbySV40orotherpolyomavirusescanresultintwopossibleoutcomes:Productive(lytic)infectionNon-productive(abortive)infectionTheoutcomeofinfectionappearstobedeterminedprimarilybythecelltypeinfected;e.g.mousepolyomavirusestablishesalyticinfectionofmousecellsbutanabortiveinfectionofratorhamstercells,whileSV40showslyticinfectionofmonkeycellsbutabortiveinfectionofmousecells.Inadditiontotranscription,T-antigenisalsoinvolvedinSV40genomereplication.SV40DNAreplicationisinitiatedbybindingoflargeT-antigentotheoriginregionofthegenome.精选课件SV40T-AntigenTheSV40genomeisverysmall&doesnotencodealltheinformationnecessaryforDNAreplication.Therefore,itisessentialforthehostcelltoenterSphase,whencellDNA&thevirusgenomearereplicatedtogether.Protein-proteininteractionsbetweenT-antigen&DNApolymeraseadirectlystimulatereplicationofthevirusgenome.ThepreciseregionsoftheT-antigeninvolvedinbindingtoDNA,DNApolymerasea,p53&Rbareallknown.InactivationoftumoursuppressorproteinsboundtoT-antigencausesG1-arrestedcellstoenterSphase÷&thisisthemechanismwhichresultsintransformation.ThefunctionofT-antigenistoalterthecellularenvironmenttopermitvirusDNAreplication.Thefrequencywithwhichabortivelyinfectedcellsaretransformedislow(about1x10-5)-transformationisarare&accidentalconsequenceofthesequestrationoftumoursuppressorproteins.精选课件Protein-BindingDomainsof

SV40T-Antigen精选课件CellTransformationbyAdenovirusesTheimmediateearlyproteinsofadenovirusesareanalogousinmanywaystoSV40T-antigen.E1Aisatrans-actingtranscriptionalregulatoroftheadenovirusearlygenes.LikeT-antigen,theE1AproteinbindstoRb,inactivatingtheregulatoryeffectofthisprotein,permittingvirusDNAreplication&accidentallystimulatingcellularDNAreplication.E1Bbindsp53&reinforcestheeffectsofE1A.ThecombinedeffectofthetwoproteinscanbeseeninthephenotypeofcellstransfectedwithDNAcontainingthesegenes.However,theinteractionofthesetransformingproteinswiththecellismorecomplexthansimpleinductionofDNAsynthesis.ExpressionofE1Aalonecausescellstoundergoapoptosis.ExpressionofE1A&E1Btogetherovercomesthisresponse&permitstransformedcellstosurvive&grow.精选课件CellTransformationbyPapillomavirusesHumanpapillomavirus(HPV)genitalinfectionsareverycommon,occurringinmorethan50%ofyoung,sexuallyactiveadults,&areusuallyasymptomatic.CertainserotypesofHPVappeartobeassociatedwithalowriskofsubsequentdevelopmentofanogenitalcancerssuchascervicalcarcinoma,afteranincubationperiodofseveraldecades.500,000newcasesofcervicalneoplasiaarediagnosedeveryyear,makingthisoneofthethreemostcommoncausesofcancerdeathinwomenglobally.HPVisaprimarycauseofcervicalcancer,93%ofallcervicalcancerstestpositiveforoneormorehighrisktypeHPV.Ofthe60HPVtypescurrentlyrecognized,onlyfourseemtobeassociatedwithahighriskoftumourformation:HPV-16,18,31,45.Onceagain,transformationismediatedbytheearlygeneproductsofthevirus.Thetransformingproteinsappeartovaryfromonetypeofpapillomavirustoanother.Itappearsthattwoormoreearlyproteinsoftencooperatetogiveatransformedphenotype.精选课件CellTransformationbyPapillomavirusesAlthoughsomepapillomavirusescantransformcellsontheirown(e.g.BPV-1),othersappeartorequirethecooperationofanactivatedcellularoncogene(e.g.HPV-16/ras).Moreconfusingly,inmostcases,allorpartofthepapillomavirusgenome,includingtheputativetransforminggenes,ismaintainedinthetumourcells,whereasinsomecases(e.g.BPV-4),thevirusDNAmaybelostaftertransformation,whichmayindicateapossiblehit-and-runmechanismoftransformation.Differentpapillomavirusesappeartouseslightlydifferentmechanismstoachievegenomereplication&consequently,celltransformationmayproceedviaaslightlydifferentroute.Thereisnopositiveevidencethatadenovirusesorpolyomavirusesareinvolvedintheformationofhumantumours.Incontrast,theevidencethatpapillomavirusesarecommonlyinvolvedintheformationofmalignantpenile&cervicalcarcinomasisnowverystrong.精选课件Viruses&CancerTherearenumerousexamplesofviruseswhichcausetumoursinexperimentalanimals.Thisstimulatedalongsearchforviruseswhichmightbethecauseofcancerinhumans.Formanyyears,thissearchwasunsuccessful,somuchsothatafewscientistscategoricallystatedthatvirusesdidnotcausehumantumours.Wecurrentlyknowofatleastsixviruseswhichareassociatedwiththeformationoftumoursininfectedhumans(HHV–4/EBV,HBV,HCV,HHV-8,HPVs,HTLV).However,therelationshipbetweenvirusinfection&tumourigenesisisindirect&complex.精选课件EpsteinBarrVirus(HHV-4)In1962,DennisBurkittdescribedahighlymalignantlymphomawhosedistributioninAfricaparalleledthatofmalaria.BurkittrecognizedthatthistumourwasrareinIndia,butoccurredinIndianchildrenlivinginAfrica,&thereforelookedforanenvironmentalcause.EBVwasfirstidentifiedin1964inalymphoblastoidcelllinederivedfromanAfricanpatientwithBurkitt'slymphoma.TheassociationbetweenEBV&Burkitt'slymphomaisnotentirelyclearcut:EBViswidelydistributedworldwidebutBurkitt'slymphomaisrare.EBVisfoundinmanycelltypesinBurkitt'slymphomapatients,notjustinthetumourcells.RarecasesofEBV-negativeBurkitt'slymphomaaresometimesseenincountrieswheremalariaisnotpresent,suggestingtheremaybemorethanoneroutetothistumour.精选课件EpsteinBarrVirus(HHV-4)EBVhasadualcelltropismforhumanB-lymphocytes(generallyanon-productiveinfection)&epithelialcells,inwhichaproductiveinfectionoccurs.TheusualoutcomeofEBVinfectionispolyclonalB-cellactivation&abenignproliferationofthesecellswhichisfrequentlyasymptomaticbutsometimesproducesarelativelymilddiseaseknownasinfectiousmononucleosisorglandularfever.In1968,itwasshownthatEBVcouldefficientlytransform(i.e.immortalize)humanB-lymphocytesinvitro.ThisobservationclearlystrengthensthecasethatEBVisinvolvedintheformationoftumours.Thereisnowepidemiologicaland/ormolecularevidencethatEBVinfectionisassociatedwithatleastfivehumantumours:Burkitt'slymphoma,nasopharyngealcarcinoma,B-celllymphomasinimmunosuppressedindividuals,someclonalformsofHodgkin'sdisease,X-linkedlymphoproliferativesyndrome.精选课件EpsteinBarrVirus(HHV-4)CellulartransformationbyEBVisacomplexprocessinvolvingtheco-operativeinteractionsbetweenseveralviralproteins.TherearethreepossibleexplanationstoexplainthelinkbetweenEBV&Burkitt'slymphoma:1)EBVimmortalizesalargepoolofB-lymphocytes.Concurrently,malariacausesT-cellimmunosuppression.Thereisthusalargepooloftargetcellsinwhichathirdevent(e.g.achromosomaltranslocation)resultsintheformationofamalignantlytransformedcell.MostBurkitt'slymphomatumourscontaintranslocationsinvolvingchromosome8,resultinginactivationofthec-mycgene,whichsupportsthishypothesis.精选课件EpsteinBarrVirus(HHV-4)2)MalariaresultsinpolyclonalB-cellactivation.EBVsubsequentlyimmortalizesacellcontainingapre-existingc-myctranslocation.Thismechanismwouldbelargelyindistinguishablefromtheabove.3)EBVisjustapassengervirus!Burkitt'slymphomaalsooccursinEurope&NorthAmericaalthoughitisveryrareintheseregions;however,85%ofthesepatientsarenotinfectedwithEBV,whichimpliesthatthereareothercausesforBurkitt'slymphoma.Althoughithasnotbeenformallyproved,itseemslikelythateither(1)and/or(2)arethetrueexplanationsfortheoriginofBurkitt'slymphoma.精选课件HBV&HepatocellularCarcinoma(HCC)Hepatitisisaninflammationoftheliver&assuchisnotasingledisease.Becauseofthecentralroleoftheliverinmetabolism,manyvirusinfectionsmayinvolvetheliver.HBVinfectionhasthreepossibleoutcomes:Anacuteinfectionfollowedbycompleterecovery&immunityfromreinfection(>90%ofcases).Fulminanthepatitis,developingquickly&lastingashorttime,causingliverfailure&amortalityrateofapproximately90%(<1%ofcases).Chronicinfection,leadingtotheestablishmentofacarrierstatewithviruspersistence(about10%ofcases).精选课件HBV&HepatocellularCarcinoma(HCC)Thereareapproximately350millionchronicHBVcarriersworldwide.Thetotalpopulationoftheworldisapproximately6billion,thereforeabout5%oftheworldpopulationispersistentlyinfectedwithHBV.Allofthesechroniccarriersofthevirusareat100-200timestheriskofnon-carriersofdevelopingHCC.HCCisararetumourintheWest,whereitrepresents<2%offatalcancers.MostcaseswhichdooccurintheWestarealcohol-related&thisisanimportantcluetothepathogenesisofthetumour.However,inSouth-EastAsia&inChina,HCCisthemostcommonfatalcancer,causingabouthalfamilliondeathseveryyear.Thevirusmightcausetheformationofthetumourbythreedifferentpathways:directactivationofacellularoncogene(s),trans-activationofacellularoncogene(s),orindirectlyviatissueregeneration.精选课件HBV&HepatocellularCarcinoma(HCC)精选课件HBV&HepatocellularCarcinoma(HCC)AswithEBV&Burkitt'slymphoma,therelationshipbetweenHBV&HCCisnotclearcut:Cirrhosis(ahardeningoftheliverwhichmaybetheresultofinfectionsorvarioustoxins,e.g.alcohol)appearstobeaprerequisiteforthedevelopmentofHCC.Itwouldappearthatchronicliverdamageinducestissueregeneration&thatfaultyDNArepairmechanismsresulteventuallyinmalignantcelltransformation.Unrelatedviruseswhichcausechronicactivehepatitis,suchastheflavivirushepatitisCvirus(HCV),arealsoassociatedwithHCCafteralonglatentperiod.Anumberofco-factors,suchasaflatoxins&nitrosamines,caninduceHCC-liketumoursinexperimentalanimalswithoutvirusinfection.SuchsubstancescouldalsobeinvolvedinhumanHCC.ThereisnoconsistentevidencefortheintegrationoftheHBVgenomeoreventhepersistenceofparticularHBVgenes(e.g.theXgene,whichencodesatrans-activatorproteinfunctionallyanalogoustotheHTLVtaxprotein)intumourcells.精选课件New&EmergentVirusesTherearenumerousexamplesofsuchviruseswhichappeartohavemysteriouslyalteredtheirbehaviourwithtime,withsignificanteffectsontheirpathogenesis.Oneexampleofthisphenomenonispoliovirus.Itisknownthatpoliovirus&poliomyelitishaveexistedinhumanpopulationsforatleast4,000years.Formostofthistime,thepatternofdiseasewasendemicratherthanepidemic,i.e.alow,continuouslevelofinfectioninparticulargeographicalareas.Duringthefirsthalfthetwentiethcentury,thepatternofoccurrenceofpoliomyelitisinEurope,NorthAmerica&Australiachangedtoanepidemicone,withvastannualoutbreaksofinfantileparalysis.Althoughwedonothavesamplesofpoliovirusesfromearliercenturies,theclinicalsymptomsofthediseasegivenoreasontobelievethattheviruschangedsubstantially.Whythendidthepatternofdiseasechangesodramatically?精选课件PoliomyelitisInruralcommunitieswithprimitivesanitationfacilities,polioviruscirculatedfreely.Serologicalsurveysinsimilarcontemporarysituationsrevealthatmorethan90%ofchildrenof3yearsofagehaveantibodiestoatleastoneofthethreeserotypesofpoliovirus.Eventhemostvirulentstrainsofpolioviruscause100-200subclinicalinfectionsforeachcaseofparalyticpoliomyelitisseen.Insuchcommunities,infantsexperiencesubclinicalimmunizinginfectionswhilestillprotectedbymaternalantibodies-aformofnaturalvaccination.Therelativelyfewcasesofparalysis&deathwhichdooccurarelikelytobeoverlooked,especiallyinviewofhighinfantmortalityrates.精选课件PoliomyelitisDuringthenineteenthcentury,industrialization&urbanizationchangedthepatternofpoliovirustransmission.Denseurbanpopulations&increasedtravellingaffordedopportunitiesforrapidtransmissionofthevirus.Inaddition,improvedsanitationbrokethenaturalpatternofvirustransmission.Childrenwerelikelytoencounterthevirusforthefirsttimeatalaterage&withouttheprotectionofmaternalantibodies.Thesechildrenwereatfargreaterriskwhentheydideventuallybecomeinfected&itisbelievedthatthesesocialchangesaccountforthealteredpatternofdisease.Fortunately,thewidespreaduseofpoliovirusvaccineshassincebroughtthesituationundercontrolinindustrializedcountries,&globaleradicationofpoliovirusisanticipatedby2005.精选课件New&EmergentVirusesTherearemanyexamplesoftheepidemicspreadofvirusescausedbymovementofhumanpopulations.Measles&smallpoxwerenotknowntotheancientGreeks.Bothofthesevirusesaremaintainedbydirectperson-to-persontransmission&havenoknownalternativehosts.IthasbeensuggestedthatitwasnotuntilhumanpopulationsinChina&theRomanEmpirereachedacriticaldensitythattheseviruseswereabletopropagateinanepidemicpattern&causerecognizableoutbreaksofdisease.Beforethistime,thefewcasesthatdidoccurcouldeasilyhavebeenoverlooked.精选课件SmallpoxSmallpoxreachedEuropefromtheFarEastin710AD&intheeighteenthcentury,achievedplagueproportions-fivereigningEuropeanmonarchsdiedfromsmallpox.However,theworsteffectsoccurredwhenthesevirusesweretransmittedtotheNewWorld.Smallpoxwas(accidentally)transferredtotheAmericasbyHernandoCortésin1520.Inthenexttwoyears,3.5millionAztecsdiedfromthedisease&theAztecempirewasdecimatedbydiseaseratherthanconquest.Althoughnotashighlypathogenicassmallpox,epidemicsofmeaslessubsequentlyfinishedofftheAztec&Incacivilizations.Morerecently,thefirstcontactswithisolatedgroupsofEskimos&tribesinNewGuinea&SouthAmericahavehadsimilarlydevastatingresults,althoughonasmallerscale.Thesehistoricalincidentsillustratethewayinwhichaknownviruscansuddenlycauseillness&deathonacatastrophicscalefollowingachangeinhumanbehaviour.精选课件VirusTransmissionPatternsMeasles&smallpoxvirusesaretransmittedexclusivelyfromonehumanhosttoanother.Forviruseswithmorecomplexcyclesoftransmission,e.g.thosewithsecondaryhosts&insectvectors,controlofinfectionbecomesmuchmoredifficult.Thisisparticularlytrueofthefamiliesofvirusesknowncollectivelyas'arboviruses'(arenaviruses,bunyaviruses,flaviviruses&togaviruses).Ashumanterritoryhasexpanded,thishasincreasinglybroughtpeopleintocontactwiththetypeofenvironmentwherethesevirusesarefound-warm,humid,vegetatedareaswhereinsectvectorsoccurinhighdensities,suchasswamps&jungles.Inadditiontochangesinagriculturalpractices,manyemergentvirusdiseasesarezoonoses,i.e.transmittedfromanimalstohumans.Thisemphasisestheimportanceofthe'speciesbarrier'inpreventingtransmissionofinfectiousdiseases.精选课件VirusTransmissionPatterns精选课件DengueFeverDenguefeverisalsoprimarilyanurbandiseaseofthetropics,transmittedbyAedesaegypti,adomestic,day-bitingmosquitothatpreferstofeedonhumans.Someoutbreaksofdenguefeverhaveinvolvedmorethanamillioncaseswithattackratesofupto90%ofthepopulation.Therearebelievedtobeover40millioncasesofDenguevirusinfectionworldwideeachyear.Thisdiseasewasfirstdescribedin1780&by1906itwasknownthattheviruswastransmittedbymosquitoes&theviruswasisolatedin1944.Therefore,thisisnotanewvirus,butthefrequencyofDenguevirusinfectionhasincreaseddramaticallyinthelasttwentyyearsduetofactorssuchas:精选课件DengueFeverPopulationmovements&theintrusionofhumans&domesticanimalsintonewarthropodhabitats,particularlytropicalforestsDeforestation,withdevelopmentofnewforest-farmlandmargins&exposureoffarmers&domesticanimalstonewarthropodsIrrigation,especiallyprimitiveirrigationsystemswhichareoblivioustoarthropodcontrolUncontrolledurbanization,withvectorpopulationsbreedinginaccumulationsofwater(tincans,oldtyres,etc.)&sewageIncreasedlong-distanceairtravel,withpotentialfortransportofarthropodvectorsIncreasedlong-distancelivestocktransportation,withpotentialforcarriageofviruses&arthropods(especiallyticks)Newroutingoflong-distancebirdmigrationbroughtaboutbynewman-madewaterimpoundmentsCessationofmosquitocontrolprogrammes&politicalupheavalresultingindegradedprimarymedicalservices精选课件ArbovirusesOfmorethan520arbovirusesknown,atleast100arepathogenicforhumans&lotswouldmeetthecriteriaforemergentviruses.Attemptstocontrolthesediseasesrelyontwinapproachesinvolvingboththecontrolofinsectvectorsresponsiblefortransmissionofthevirustohumans&thedevelopmentofvaccinestoprotecthumanpopulations.However,bothoftheseapproachespresentconsiderabledifficulties,bothinavoidingenvironmentaldamage&understandingviruspathogenesis&developingappropriatevaccines:RiftValleyFeverviruswasfirstisolatedfromsheepin1930buthascausedrepeatedepidemicsinsub-SaharanAfricaduringthelast20years,withhumaninfectionratesinepidemicareasashighas35%.Thisisanepizooticdisease,transmittedfromsheeptohumansbyanumberofdifferentmosquitoes.Theconstructionofdamswhichincreasemosquitopopulations,increasingnumbersofsheep&themovementofsheep&humanpopulationsarebelievedtoberesponsiblefortheupsurge.精选课件WestNileVirusWestNilevirusisamemberoftheJapaneseencephalitisantigeniccomplexofthegenusFlavivirus,familyFlaviviridae.Allknownmembersofthiscomplexaretransmissiblebymosquitoes&manyofthemcancausefebrile,sometimesfatal,illnessesinhumans.WestNileviruswasfirstisolatedintheWestNiledistrictofUgandain1