Staphylococcusaureus(S.aureus)isaubiquitousgram-positivepathogenthatisoneofthe mostfrequentcausesofskinandsofttissueinfections.Frequently,theseinfectionsserveasa preludetoinvasivelife-threateningdiseases.TheprevalenceofsevereS.aureusinfections haveincreasedinhealthypopulations,associatedwiththedevelopmentofbothdrugresistance andhypervirulenceinmethicillin-resistantS.aureus(MRSA)strainssuchUSA300.Thespread ofMRSA-induceddiseaseduringtrainingandmissionassignmentsisawell-documentedthreat tomilitarypublichealth.Awealthofbothclinicalandexperimentalevidencesuggeststhat(1) neutrophils(PMNs)areessentialmediatorsofanti-S.aureushostdefense,and(2)emerging MRSAstrainsreleasetoxinscapableofkillingPMNs,andconsequentlytheycanoverwhelm hostdefenseresponsesandrapidlycausediseaseinimmunecompetentindividuals.The rapidityoftheseeventssuggestsaprotectivevaccinewouldbethebestapproachtodisease control.UsingamodelofhealedMRSAskininfectionthatelicitsprotectiveimmunityagainsta secondMRSAskininfection,weprovideevidencethattheappropriateinductionofhumoraland cellularimmuneresponsescanseparatelybutsynergisticallysupportanti-MRSAeffector responsesandexpeditepathogenclearance.Theresearchplandescribedhereinwilltestthe hypothesesthatactiveimmunizationagainstS.aureusisfeasible,andthatprotectiveantigens includesecretedbacterialvirulencefactors.
The specificaims aredesignedtoevaluatethe pathogenandhost-derivedfactorsthatarerequiredtoinitiateandmaintainant-MRSA protectiveadaptiveimmuneresponses.
In specificaim1 wewillidentifyantigensleadingto protectiveimmunitybysystematicallymeasuringtheprophylacticeffectsofskinchallengewith selectedknockoutstrainsofMRSAfollowedbyrechallengewithWTMRSA.
In aim2, wewill characterizeTfollicularhelperandthegerminalcenterresponsesthatcorrespondwithanti- MRSAprotectiveimmunity,andemployLangerin-DTRmicetodelineatetheskinDC requirementsfortheseprocesses.
In aim3, wewillcharacterizethe cutaneousTcellsignature correspondingwithanti-MRSAprotectiveimmunitybymeasuringthekineticsandtissue distributionpathogenspecificTcellsfollowinginfectionwithstrainsofMRSAthathavebeen engineeredtoexpressovapeptideOVA 323-339.AfterclarifyingtheadaptiveTcellcorrelatesof anti-MRSAprotectiveimmunity,wewillusetheLangerin-DTRsystemtoelucidatethe underlyingDCrequirementsfortheirinduction.Overalltheprogramisdesignedtodissectthe humoralandcellularimmunecomponentsrequiredforaprotectiveimmuneresponsetoMRSA. Onceexplored,thesedatawillprovidethebasistodesignandevaluateapproachestoa preventivevaccine.
Staphylococcusaureus(S.aureus)isoneofthemostfrequentcausesofskinandsofttissue infections.S.aureusinfectionsoftenspreadtointernalsitesandcauseinvasivelife-threatening diseases.TherehasbeenanincreaseinsevereS.aureusinfectionsinhealthyindividuals, associatedwiththespreadofdrugresistantstrainswithheightenedvirulencemechanisms. Becauseoftheirrapiddevelopment,aprotectivevaccinewouldbethemosteffectivewayto preventseriousstaphylococcaldisease.Weproposeinthisapplicationtodefinethe characteristicsofprotectiveimmunitytoS.aureus.Insodoing,wewillprovidetheneeded backgroundfordesignofapreventivevaccine.
