Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions.docVIP

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Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions.doc

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Anthrax Lethal Toxin Downregulates Claudin-5 Expression in Human Endothelial Tight Junctions

AnthraxLethalToxinDownregulatesClaudin-5 ExpressioninHumanEndothelialTightJunctions FeliceD’Agnillo1*,MatthewC.Williams1,MahtabMoayeri3,JasonM.Warfel2 1Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, United States of America, 2Laboratory of Respiratory and Special Pathogens, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics EvaluationandResearch,FoodandDrugAdministration,Bethesda,Maryland,UnitedStatesofAmerica,3MicrobialPathogenesisSection,LaboratoryofParasiticDiseases, NationalInstituteofAllergyandInfectiousDiseases,NationalInstitutesofHealth,Bethesda,Maryland,UnitedStatesofAmerica Abstract Vascularleakagepathologiessuchaspleuraleffusionandhemorrhagearehallmarksofanthraxpathogenesis.Wepreviously reportedthatanthraxlethaltoxin(LT),themajorvirulencefactorofanthrax,reducesbarrierfunctioninculturedprimary humanmicrovascularendothelialcells.Here,weshowthatLT-inducedbarrierdysfunctionisaccompaniedbythereduced expressionoftheendothelialtightjunction(TJ)proteinclaudin-5butnochangeintheexpressionofotherTJcomponents occludin, ZO-1, ZO-2, or the adherens junction (AJ) protein VE-cadherin. The downregulation of claudin-5 correlated temporallyanddose-dependentlywiththereductionoftransendothelialelectricalresistance.LT-inducedlossofclaudin-5 was independent of cell death and preceded the appearance of actin stress fibers and altered AJ morphology. PharmacologicalinhibitionofMEK-1/2,twokinasesthatareproteolyticallyinactivatedbyLT,showedasimilarreductionin claudin-5 expression. We found that LT reduced claudin-5 mRNA levels but did not accelerate the rate of claudin-5 degradation.MicechallengedwithLTalsoshowedsignificantreductioninclaudin-5expression.Together,thesefindings supportapossibleroleforLTdisruptionofendothelialTJsinthevascularleakagepathologiesofanthrax. Citation: D’Agnillo F, Williams MC, Moayeri M, Warfel JM (2013) Anth