Project Grant R01AI183590

PATHOGENESIS OF ALPHAVIRUS INDUCED CHRONIC ARTHRITIS AND MYOSITIS - SUMMARY. CHIKUNGUNYA VIRUS (CHIKV) IS AN EMERGING MOSQUITO-TRANSMITTED ALPHAVIRUS THAT CAUSES AN ABRUPT ONSET OF FEVER WITH SEVERE JOINT AND MUSCLE PAIN. IN A SIGNIFICANT FRACTION OF PATIENTS, CHRONIC AND DEBILITATING ARTHRITIS CAN DEVELOP AND PERSIST FOR MONTHS TO YEARS, WITH RECENT EPIDEMIOLOGICAL PROJECTIONS SUGGESTING THERE ARE MORE THAN 400,000 PATIENTS IN THE WESTERN HEMISPHERE ALONE WITH CHRONIC CHIKV MUSCULOSKELETAL DISEASE. PATIENTS AFFECTED BY CHRONIC CHIKV DISEASE SHOW ELEVATED SYNOVIAL PROINFLAMMATORY CYTOKINES AND INFILTRATING CELLS INCLUDING MONOCYTES AND CD4+ T CELLS. IN ADDITION, PERSISTENT CHIKV RNA IS DETECTED IN HUMAN PATIENTS, NON-HUMAN PRIMATES, AND MICE FOR MONTHS TO YEARS AFTER INFECTION. TO IDENTIFY THE CELLS THAT HARBOR THIS RNA DURING THE CHRONIC PHASE OF DISEASE, WE RECENTLY ENGINEERED A RECOMBINANT CHIKV TO EXPRESS CRE RECOMBINASE AND DEMONSTRATED THAT THE INFECTION OF TDTOMATO REPORTER MICE RESULTED IN PERSISTENT TDTOMATO+ CELLS. TO DATE, OUR ANALYSIS HAS REVEALED THAT FIBROBLASTS AND MACROPHAGES ARE KEY CELL TYPES THAT HARBOR VIRAL RNA IN THE CHRONIC PHASE. THEREFORE, THIS SYSTEM ALLOWS US TO TEST THE HYPOTHESIS THAT DURING CHRONIC DISEASE, A SUBSET OF CHIKV INFECTED CELLS SURVIVE INFECTION AND HARBOR PERSISTENT, NON-PRODUCTIVELY REPLICATING VIRAL RNA THAT FUNCTIONS AS A PATHOGEN ASSOCIATED MOLECULAR PATTERN (PAMP) TO DRIVE PERSISTENT INFLAMMATION. THE PREMISE OF THIS PROPOSAL IS TO UTILIZE THIS CHIKV LINEAGE TRACING SYSTEM IN A MURINE MODEL OF CHIKV ARTHRITIS TO IDENTIFY, ISOLATE, AND CHARACTERIZE THE CELLS THAT ARE INFECTED, SURVIVE CHIKV INFECTION, AND HARBOR VIRAL RNA. WE WILL TEST THE HYPOTHESIS THAT THIS PERSISTENT RNA ACTIVATES PATTERN RECOGNITION RECEPTORS DURING ACUTE AND CHRONIC DISEASE DRIVING INFLAMMATORY PHENOTYPES IN BOTH MACROPHAGES AND FIBROBLASTS. THESE STUDIES WILL PROVIDE IMPORTANT NEW INSIGHT INTO THE PATHOGENESIS OF CHRONIC CHIKV ARTHRITIS AND POSSIBLY CREATE NEW AVENUES FOR THERAPEUTIC INTERVENTIONS.