The overarching goal of my research program is to understand the molecular mechanisms of immune surveillancemediatedbytissue-residentmemoryTcellsthatpatrolthemucosalbarrierofthelungstocontrol infectiousdiseasesandcancers.Mylaboratoryisbestrecognizedforitscontributionstothecellbiologyand biochemistry of MHC and MHC-like CD1d molecules. These molecules play important roles in protein and lipidantigenpresentationand,thereby,controlTcellandnaturalkillerT(NKT)cellbiology,respectively.In recentyears,ourresearchfocushasturnedtowardharnessingwhatwehavelearntinbasicimmunologyto augmentimmunereactionthroughvaccineandadjuvantdesigntopreventortreatmicrobialinfectionsand cancer,deathlydiseasesthatailhumankind:WerecentlyreportedastrategyforCD8+Tcell-targetedvaccine designtoidentifytargetsthatconferprotectiveimmunityagainstpoxvirusdisease(J.Clin.Invest.123:1976? 1987;?2013).Usingthismodel,wehaveelucidatedthemechanismsofinduction,maintenanceandactionof tissueresidentmemory(Trm)CD8+TcellsandhowTrmcellsimpartlung/pulmonarymucosalimmunity(Cell Rep16:1800;?2016).NewworksupportedbytheResearchCareerScientistandtheVAMeritwillrefinethe abovestrategiestodevisewaystoidentify,characterizeanddevelopvaccinecandidatesagainsttuberculosis.
Aims of this project are, (a) to identify T cell epitopes that will protect against pulmonary M tuberculosis infectioninapreclinicalhumanizedmousemodel;?(b)toidentifygloballyprotectiveepitopesthatcrossMHC restriction barriers;? and (c) to characterize nanoparticle-based delivery systems for intracellular STING- targeted adjuvant and antigen delivery. Hence, as a Research Career Scientist, I hope to identify T cell epitopesthatwillprotectagainsttuberculosisanddevisewaystoenhanceimmunologicalmemoryatthelung mucosalsurfacesbyvaccinatingwithsubunitvaccinesandintracellularadjuvants.Thisoutcomewillimpact clinicalmanagementoftuberculosisaswellasotherrespiratoryinfectiousdiseasesandcancers. My research program was developed through numerous collaborations with investigators at the VA, the UniversityAffiliate,theNIH,andatnationalandinternationalinstitutions.Ihavepublishedover120articles, severalintop-tierjournals.Theseworkshavebeencitedover9,700times,andhaveanh-indexof48andan i10-indexof93.Significantly,ourresearchhasbeencontinuouslysupportedbyfederalgrantsoverthelast 20+yearsandbyaVAMeritAwardoverthelastfouryears.Insum,Iamwell-poisedtoserveourVeterans as a Research Career Scientist. Through this appointment, I hope to enhance research in vaccines and vaccinedeliverymechanismsthatwillutilizeTcellepitopes.Theemergingvaccinesanddeliverymechanisms willenhanceimmunologicalmemoryatthelungmucosalsurfacesthroughvaccinationwithsubunitvaccines andintracellularadjuvantstomediateprotectiveimmunityagainstinfectiousdiseasesandcancers. OurVeteransareexposedtodeathlyinfectiousdiseases,suchastuberculosisandcancers.Forexample, the wars in Afghanistan and Iraq as well as deployment in Korea and other South Eastern countries have contributedtothetuberculosisincidenceintheUSMilitary.Arecentstudyidentified113VeteransinWestern USwithconfirmedtuberculosisdiagnosisbetween2010?2013.Theincidencehassincerisenamongstour Veterans. Another study noted that of the 42 Veterans diagnosed with latent TB, only ~43% had initiated treatment and only ~31% had completed the drug regimen. This foretells a grim situation as the untreated Veteran population, especially those with latent TB infection, are potential disease transmitters;? still worse, those that do not complete the drug regimen can raise drug-resistant strains for transmission. Hence, our research and its outcomes will directly impact clinical practice paradigms against tuberculosis and other respiratoryinfectiousdiseases.Thus,ourresearchwillbetterthelivesofVeterans.
OurVeteransaresusceptibletoavarietyofrespiratoryinfectionssuchaswithMycobacteriumtuberculosis.M tuberculosiscausesthechronicinfectiousdiseasetuberculosis(TB)thathashighmorbidityandmortality.The globalburdenofTBcontinuestoincreasewiththeemergenceofmultidrug-resistantandextremelydrugresistant MtuberculosisstrainsandthelackofaneffectivevaccinethatprotectsadultsfrominfectionandtheensuingTB disease. As a Research Career Scientist, I will develop an effective and durable vaccine that can protect our VeteransfromTBandpotentiallyotherrespiratoryinfectiousdiseases.AsMtuberculosisistransmittedthrough aerosols and infects the lung mucosa, the challenge is to install immune effector cells at this site. My collaboratorsandIhavefoundwaystoinstallpathogen-specificimmuneeffectorsatthelungmucosa.Usingthis strategy,wewilldevelopandtestadurablevaccineagainstTBinapreclinicalmodel.Thisworkwillleadtothe designofaclinicalvaccineagainstTBandotherdiseases,and,hence,betterthequalityoflivesofourVeterans.
