Oneofthekeycausesofanthraxvirulenceistheproductionofthreespecificfactorsbythegram-positivesporeformingbacteriaBacillusanthracis.Evenwithsuccessfulantibiotictreatment,anthraxtoxinscanremaininthecirculationandcauselethality.Thetoxinsproducedbyanthraxbacteriaarederivedfromthreegenes:lethalfactor(LF),protectiveantigen(PA)andedemafactor(EF).TheentryoftoxinintocellsbeginswiththerecognitionofarecentlyidentifiedcellularreceptorintheplasmamembranebyPA.Proteolyticcleavageofcell-boundPAcreatesasmallerfragmentthatthenmultimerizesintoapore-likestructureintheplasmamembrane.TheLFandEFproteinsbindtothePApre-pore,followedbyinternalizationoftheentirestructurethroughreceptor-mediatedendocytosis.Intheendosomalcompartment,theacidicpHcausesaconformationalchangethatinsertsPAfragmentsandreleasesLFandEFintothecytoplasm.Inthecytoplasm,LFactsasaproteasethatcleavesMAPkinasekinase(MAPKK1andMAPKK2),inhibitingpathwaysthatrelyonthiskinasefamilyandcausingcelldeath.Edemafactorisanadenylatecyclasethatinhibitstheimmuneresponse,includingphagocytosisbymacrophages.Severalpotentialmechanismscouldbeusedtoblockanthraxtoxinaction,oneofwhichwasdemonstratedbythedesignofamultivalentproteininhibitoroftoxininteractionwithPA.

Contributor:GlennCroston,PhD

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