Sex-Related Differences in Gene Expression Following Coxiella burnetii Infection in Mice Potential Role of Circadian Rhythm 英文参考文献.docVIP

Sex-RelatedDifferencesinGeneExpressionFollowing CoxiellaburnetiiInfectioninMice:PotentialRoleof CircadianRhythm JulienTextoris1,2,LeangHengBan1,2,ChristianCapo1,DidierRaoult1,MarcLeone1,2,Jean-LouisMege1* 1Unite′ deRecherchesurlesMaladiesInfectieusesTropicalesetEmergentes,CentreNationaldelaRechercheScientifiqueUnite′ MixtedeRecherche6236,Faculte′ de Me′decine,Marseille,France,2Serviced’anesthe′sieetdere′animation,Ho?pitalNord,AssistancePublique–Ho?pitauxdeMarseille,Universite′ delaMe′diterrane′e,Marseille, France Abstract Background: Q fever, a zoonosis due to Coxiella burnetii infection, exhibits sexual dimorphism; men are affected more frequentlyandseverelythanwomenforagivenexposure.HereweexplorewhethertheseverityofC.burnetiiinfectionin miceisrelatedtodifferencesinmaleandfemalegeneexpressionprofiles. Methodology/PrincipalFindings:MicewereinfectedwithC.burnetiifor24hours,andgeneexpressionwasmeasuredin livercellsusingmicroarrays.Multiclassanalysisidentified2,777probesforwhichexpressionwasspecificallymodulatedby C.burnettiinfection.Only14%ofthemodulatedgenesweresex-independent,andtheremaining86%weredifferentially expressedinmalesandfemales.Castrationofmalesandfemalesshowedthatsexhormoneswereresponsibleformorethan 60%oftheobservedgenemodulation,andthisreductionwasmostpronouncedinmales.Usingfunctionalannotationof modulatedgenes,weidentifiedfourclustersenrichedinmalesthatwererelatedtocell-celladhesion,signaltransduction, defensins and cytokine/Jak-Stat pathways. Up-regulation of the IL-10 and Stat-3 genes may account for the high susceptibility of men with Q fever to C. burnetii infection and autoantibody production. Two clusters were identified in females, including the circadian rhythm pathway, which consists of positive (Clock, Arntl) and negative (Per) limbs of a feedbackloop.WefoundthatClockandArntlweredown-modulatedwhereasPerwasup-regulated;thesechangesmaybe associatedwithefficientbacterialeliminationinfemalesbutnotinmales,inwhichanexacerbatedh