Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p 英文参考文献.docVIP

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Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p 英文参考文献.doc

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Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p 英文参考文献

Calcium-Activated-CalcineurinReducestheInVitroand InVivoSensitivityofFluconazoletoCandidaalbicansvia Rta2p YuJia1,2.,Ren-JieTang1.,LinWang1,XiangZhang3,YingWang4,Xin-MingJia2*,Yuan-YingJiang1* 1School of Pharmacy, Second Military Medical University, Shanghai, China, 2Department of Immunology, Tongji University School of Medicine, Shanghai, China, 3DepartmentofNeurosurgery,TenthPeople’sHospital,TongjiUniversitySchoolofMedicine,Shanghai,China,4DepartmentofDermatology,ChanghaiHospital,Second MilitaryMedicalUniversity,Shanghai,China Abstract Duetotheemergenceofdrug-resistance,first-linetherapywithfluconazole(FLC)increasinglyresultedinclinicalfailurefor the treatment of candidemia. Our previous studies found that invitro RTA2 was involved in the calcineurin-mediated resistancetoFLCinC.albicans.Inthisstudy,wefoundthatcalcium-activated-calcineurinsignificantlyreducedtheinvitro sensitivityofC.albicanstoFLCbyblockingtheimpairmentofFLCtotheplasmamembraneviaRta2p.Furthermore,we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeuticefficacyofFLCinamurinemodelofsystemiccandidiasis.Conversely,bothre-introductionofoneRTA2allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium- activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the criticalrolesofRta2pincontrollingtheefficacyofFLC,Rta2pcanbeapotentialdrugtargetforantifungaltherapies. Citation: JiaY,TangR-J,WangL,ZhangX,WangY,etal.(2012)Calcium-Activated-CalcineurinReducesthe InVitroandInVivoSensitivityofFluconazoleto CandidaalbicansviaRta2p.PLoSONE7(10):e48369.doi:10.1371/journal.pone.0048369 Editor:GustavoHenriqueGoldman,UniversidadedeSaoPaulo,Brazil ReceivedMay21,2012;AcceptedSeptember24,2012;PublishedOctober30,2012 Copyright:?2012Jiaetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttri