A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major 英文参考文献.docVIP

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A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major 英文参考文献.doc

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A Novel Role for Stat1 in Phagosome Acidification and Natural Host Resistance to Intracellular Infection by Leishmania major 英文参考文献

ANovelRoleforStat1inPhagosomeAcidificationand NaturalHostResistancetoIntracellularInfectionby Leishmaniamajor GeraldF.Spa¨th1,2,3,PaulSchlesinger4,RobertSchreiber5,StephenM.Beverley1* 1Department of Molecular Microbiology, Washington University Medical School, St. Louis, Missouri, United States of America, 2Department of Parasitology and Mycology, Laboratory of Parasite Virulence, Institut Pasteur, Paris, France, 3Institut National de la Sante′ et de la Recherche Me′dicale (INSERM) AVENIR, Paris, France, 4Department of Cell Biology, Washington University Medical School, St. Louis, Missouri, United States of America, 5Department of Pathology and Immunology, WashingtonUniversityMedicalSchool,St.Louis,Missouri,UnitedStatesofAmerica Abstract IntracellularparasitesofthegenusLeishmaniagenerateseverediseasesinhumans,whichareassociatedwithafailureof the infected host to induce a protective interferon c (IFNc)-mediated immune response. We tested the role of the JAK/ STAT1signalingpathwayinLeishmaniapathogenesisbyutilizingknockoutmicelackingthesignaltransducerandactivator oftranscription 1(Stat1)andderivedmacrophages. Unexpectedly,infectionofStat1-deficient macrophages invitro with promastigotesfromLeishmaniamajorandattenuatedLPG1knockoutmutants(lpg2)specificallylackinglipophosphoglycan (LPG)resultedinatwofoldincreasedintracellulargrowth,whichwasindependentofIFNcandassociatedwithasubstantial increase in phagosomal pH. Phagosomes in Stat12/2 macrophages showed normal maturation as judged by the accumulationofthelysosomalmarkerproteinrab7,andprovidednormalvATPaseactivity,butweredefectiveintheanion conductive pathway required for full vesicular acidification. Our results suggest a role of acidic pH in the control of intracellularLeishmaniagrowthearlyduringinfectionandidentifyforthefirsttimeanunexpectedroleofStat1innatural anti-microbialresistanceindependentfromitsfunctionasIFNc-inducedsignaltransducer.ThisnovelStat1functionmay have important implications to studies of othe