Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection 英文参考文献.docVIP

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Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection 英文参考文献.doc

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Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection 英文参考文献

EchinocandinTreatmentofPneumocystisPneumoniain RodentModelsDepletesCystsLeavingTrophicBurdens ThatCannotTransmittheInfection MelanieT.Cushion1,2*,MichaelJ.Linke2,AlanAshbaugh1,2,TomSesterhenn1,2,MargaretS.Collins1,2 , KeeleyLynch1,2,RonaldBrubaker3,PeterD.Walzer1,2 1CollegeofMedicine,UniversityofCincinnati,Cincinnati,Ohio,UnitedStatesofAmerica,2VeteransAdministrationMedicalCenter,Cincinnati,Ohio,UnitedStatesof America,3DepartmentofPathology,TheChristHospital,Cincinnati,Ohio,UnitedStatesofAmerica Abstract FungiinthegenusPneumocystiscausepneumonia(PCP)inhostswithdebilitatedimmunesystemsandareemergingasco- morbidityfactorsassociatedwithchronicdiseasessuchasCOPD.Limitedtherapeuticchoicesandpoorunderstandingof thelifecyclearearesultoftheinabilityofthesefungitogrowoutsidethemammalianlung.Withinthealveolarlumen, Pneumocystisspp., appear tohaveabi-phasiclife cycle consisting ofanasexualphasecharacterized by binaryfission of trophicformsandasexualcycleresultinginformationofcysts,butthelifecyclestagethattransmitstheinfectionisnot known.Thecysts,butnotthetrophicforms,expressb-1,3-D-glucansynthetaseandcontainabundantb-1,3-D-glucan.Here weshowthattherapeuticandprophylactictreatmentofPCPwithechinocandins,compoundswhichinhibitthesynthesisof b -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers.Survivalwasenhancedintheechincandintreatedmice,likelyduetothedecreasedb-1,3-D-glucancontentinthe lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology.Strongevidenceforthecystastheagentoftransmissionwasprovidedbythefailureofanidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppressionpermittedtherepopulationofcystforms.TreatmentofPCPwithanechinocandinalonewillnotlikely result in eradicationof infectionandcessation ofechinocandin treatmentwhile thepa