Role of TLR signaling in Francisella tularensis‐LPS‐induced, antibody‐mediated protection against Francisella tularensis challenge

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: B cells;    bacterial infection;    antibodies;    vaccination;    macrophage activation;    adjuvants;   

DOI  :  10.1189/jlb.0111014

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

ImmunizationwithFt‐LPSprovokesanantigen‐specific,B‐1acell‐derivedantibodyresponsethatprotectsWTmiceagainstanotherwiselethalchallengewithFtLVS.However,thissameregimenofferslimitedprotectiontoTLR2−/−mice,despiteproductionofWTlevelsofanti‐Ft‐LPSantibodies.AsFt‐LPSexhibitsnoTLR2agonistactivity,andmacrophage‐inducedcytokineproductioninresponsetoFtLVSisoverwhelminglyTLR2‐dependent,wehypothesizedthattreatmentofTLR2−/−micewithanalternative,MyD88‐dependentTLRagonistwouldcompensateforreducedrecognitionofFtLVSinTLR2−/−miceandthereby,restoreFt‐LPS‐mediatedprotection.AdministrationofthenontoxicTLR4agonist,syntheticEscherichiacoliMPL,atthetimeofFt‐LPSimmunizationorFtLVSchallenge,fullyprotectedTLR2−/−mice,whereastreatmentofWTorTLR2−/−micewithMPLaloneconferredpartialprotection.TheTLR5agonist,flagellin,alsosynergizedwithFt‐LPStoprotectTLR2−/−micefromlethalFtLVSchallenge.IncontrasttoFtLVS,Ft‐LPSpretreatmentfailedtoprotectmiceagainsti.n.challengewithFtSchuS4,whereasMPL,administeredintheabsenceorpresenceofFt‐LPS,conferredsignificant,albeitpartial,protection.MPLtreatmentofmacrophagesincreasedtheuptakeofFtLVSanddecreasedintracellularbacterialsurvivalwhileshiftingthemacrophage‐differentiationphenotypefrom“alternativelyactivated”to“classicallyactivated”.Collectively,ourdatasuggestthatoptimal,Ft‐LPS‐mediatedprotectionagainstFtLVSinfectionrequirestwodiscreteevents,i.e.,productionofFt‐LPS‐specificantibody,aswellasTLR‐mediatedmacrophageactivation,tofullycontrolFrancisellainfection...

【 授权许可】

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