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

REFERENCES:Beauregard,K.E.,Collier,R.J.,Swanson,J.A.Proteolyticactivationofreceptor-boundanthraxprotectiveantigenonmacrophagespromotesitsinternalization.Cell.Microbiol.2000,2(3),251-8Bradley,KA.etal.Identificationofthecellularreceptorforanthraxtoxin.Nature2001,414(6860),225-9Duesbery,N.S.etal.ProteolyticinactivationofMAP-kinase-kinasebyanthraxlethalfactor.Science1998,280(5364),734-7Leppla,S.H.Anthraxtoxinedemafactor:abacterialadenylatecyclasethatincreasescyclicAMPconcentrationsofeukaryoticcells.Proc.Natl.Acad.Sci.U.S.A.1982,79(10),3162-6Mourez,M.etal.Designingapolyvalentinhibitorofanthraxtoxin.Nat.Biotechnol.2001,(10),958-61

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