Proteomic Identification of IPSEalpha-1 as a Major Hepatotoxin Secreted by Schistosoma mansoni Eggs 英文参考文献.docVIP

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Proteomic Identification of IPSEalpha-1 as a Major Hepatotoxin Secreted by Schistosoma mansoni Eggs 英文参考文献.doc

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Proteomic Identification of IPSEalpha-1 as a Major Hepatotoxin Secreted by Schistosoma mansoni Eggs 英文参考文献

ProteomicIdentificationofIPSE/alpha-1asaMajor HepatotoxinSecretedbySchistosomamansoniEggs Maha-HamadienAbdulla1,2*,Kee-ChongLim1,JamesH.McKerrow1,ConorR.Caffrey1 1TheColorectalResearchCenter,DepartmentofSurgery,KingKhalidUniversityHospital,KingSaudUniversity,Riyadh,SaudiArabia,2SandlerCenterforDrugDiscovery andDepartmentofPathology,UniversityofCaliforniaSanFrancisco,SanFrancisco,California,UnitedStatesofAmerica Abstract Background:Eggsdepositedintheliverofthemammalianhostbythebloodflukeparasite,Schistosomamansoni ,normally driveaT-helper-2(Th2)-mediatedgranulomatousresponseinimmune-competentmice.Bycontrast,inmicedeprivedofT- cellsandincapableofproducinggranulomata,egg-secretedproteins(ESP)induceacutehepaticinjuryanddeath.Previous workhasshownthatonesuchESP,theT2ribonucleaseknownasomega-1,ishepatotoxicinvivointhatspecificantiserato omega-1preventhepatocytedamage. Methodology/Principal Findings: Using an in vitro culture system employing mouse primary hepatocytes and alanine transaminase(ALT)activityasamarkerofheptocyteinjury,wedemonstratedthatS.mansonieggs,egg-secretedproteins (ESP), soluble-egg antigen (SEA), and omega-1 are directly hepatotoxic and in a dose-dependent manner. Depletion of omega-1usingamonoclonalantibodyabolishedthetoxicityofpureomega-1anddiminishedthetoxicityinESPandSEA by 47 and 33%, respectively. Anion exchange chromatography of ESP yielded one predominant hepatotoxic fraction. ProteomicsofthatfractionidentifiedthepresenceofIPSE/alpha-1(IL-4inducingprinciplefromS.mansonieggs),aknown activatorofbasophilsandinducerofTh2-typeresponses.PurerecombinantIPSE/alpha-1alsodisplayedadose-dependent hepatotoxicity in vitro. Monoclonal antibody depletion of IPSE/alpha-1 abolished the latter’s toxicity and diminished the totaltoxicityofESPandSEAby32and35%,respectively.Combineddepletionofomega-1andIPSE/alpha-1diminished hepatotoxicityofESPandSEAby60and58%respectively. Conclusions:WeidentifiedIPSE/alpha-1asanovelhepatotoxinandconcludethatbothIPSE/alpha-1andomeg