Serine Protease(s) Secreted by the Nematode Trichuris muris Degrade the Mucus Barrier 英文参考文献.docVIP

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Serine Protease(s) Secreted by the Nematode Trichuris muris Degrade the Mucus Barrier 英文参考文献.doc

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SerineProtease(s)SecretedbytheNematodeTrichuris murisDegradetheMucusBarrier SumairaZ.Hasnain1,2,3*,MichaelA.McGuckin1,RichardK.Grencis2,DavidJ.Thornton3* 1Immunity,InfectionandInflammation,MaterMedicalResearchInstitute,Brisbane,Australia, 2ManchesterImmunologyGroup,FacultyofLifeSciences,Universityof Manchester, Manchester, United Kingdom, 3Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom Abstract Thepolymericmucincomponentoftheintestinalmucusbarrierchangesduringnematodeinfectiontoprovidenotonly physicalprotectionbutalsotodirectlyaffectpathogenicnematodesandaidexpulsion.Despitethis,thedirectinteraction ofthenematodeswiththemucinsandthemucusbarrierhasnotpreviouslybeenaddressed.Weusedthewell-established Trichuris muris nematode model to investigate the effect on mucins of the complex mixture of immunogenic proteins secretedbythenematodecalledexcretory/secretoryproducts(ESPs).DifferentregimesofT.murisinfectionwereusedto simulatechronic(lowdose)oracute(highdose)infection.Mucus/mucinsisolatedfrommiceandfromthehumanintestinal cellline,LS174T,weretreatedwithESPs.Wedemonstratethatserineprotease(s)secretedbythenematodehavetheability tochangethepropertiesofthemucusbarrier,makingitmoreporousbydegradingthemucincomponentofthemucus gel.Specifically,theserineprotease(s)actedontheN-terminalpolymerisingdomainofthemajorintestinalmucinMuc2, resultingindepolymerisationofMuc2polymers.Importantly,therespiratory/gastricmucinMuc5ac,whichisinducedinthe intestineandiscriticalforwormexpulsion,wasprotectedfromthedepolymerisingeffectexertedbyESPs.Furthermore, serineproteaseinhibitors(Serpins)whichmayprotectthemucins,inparticularMuc2,fromdepolymerisation,werehighly expressed in mice resistant to chronic infection. Thus, we demonstrate that nematodes secrete serine protease(s) to degrademucinswithinthemucusbarrier,whichmaymodifythenicheoftheparasitetopreventclearancefromthehostor facilitateefficientmatingandegglay