A Non Mouse-Adapted Dengue Virus Strain as a New Model of Severe Dengue Infection in AG129 Mice 英文参考文献.docVIP

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A Non Mouse-Adapted Dengue Virus Strain as a New Model of Severe Dengue Infection in AG129 Mice 英文参考文献.doc

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A Non Mouse-Adapted Dengue Virus Strain as a New Model of Severe Dengue Infection in AG129 Mice 英文参考文献

ANonMouse-AdaptedDengueVirusStrainasaNew ModelofSevereDengueInfectioninAG129Mice GraceK.Tan1,JowinK.W.Ng1,ScottL.Trasti2,WouterSchul3,GeorgeYip4,SylvieAlonso1* 1DepartmentofMicrobiology,ImmunologyProgramme,NationalUniversityofSingapore,Singapore,Singapore,2ComparativeMedicineCentre,NationalUniversityof Singapore, Singapore, Singapore, 3Novartis Institute for Tropical Diseases (NITD), Singapore, Singapore, 4Department of Anatomy, National University of Singapore, Singapore,Singapore Abstract Thespreadofdengue(DEN)worldwidecombinedwithanincreasedseverityoftheDEN-associatedclinicaloutcomeshave madethismosquito-bornevirusofgreatglobalpublichealthimportance.ProgressinunderstandingDENpathogenesisand indevelopingeffectivetreatmentshasbeenhamperedbythelackofasuitablesmallanimalmodel.MostoftheDENclinical isolatesandcellculture-passagedDENvirusstrainsreportedsofarrequireeitherhostadaptation,inoculationwithahigh doseand/orintravenousadministrationtoelicitavirulentphenotypeinmicewhichresults,atbest,inaproductiveinfection withno, few,orirrelevantdisease manifestations,andwithmice dying withinfewdays atthepeak ofviremia. Herewe describeanon-mouse-adaptedDEN2virusstrain(D2Y98P)thatishighlyinfectiousinAG129mice(lackinginterferon-a/b and -c receptors) upon intraperitoneal administration. Infection with a high dose of D2Y98P induced cytokine storm, massiveorgandamage,andseverevascularleakage,leadingtohaemorrhageandrapiddeathoftheanimalsatthepeakof viremia. In contrast, very interestingly and uniquely, infection with a low dose of D2Y98P led to asymptomatic viral dissemination and replication in relevant organs, followed by non-paralytic death of the animals few days after virus clearance,similartothediseasekineticinhumans.Spleendamage,liverdysfunctionandincreasedvascularpermeability, butnohaemorrhage,wereobservedinmoribundanimals,suggestingintactvascularintegrity,acardinalfeatureinDEN shock syndrome. Infection with D2Y98P thus offers the opportunity to further decipher some of