Project Grant R01AI179890

DETERMINING THE IMPACT OF STROMAL CELL-MEDIATED TYPE I IFN SIGNALING ON ALPHAVIRUS PATHOGENESIS - ABSTRACT TYPE I INTERFERONS (IFNS) ARE IMPORTANT INNATE CYTOKINES THAT INFLUENCE LOCAL AND SYSTEMIC IMMUNE RESPONSES. THEY CAN PLAY BENEFICIAL ROLES THROUGH THEIR ANTIVIRAL PROPERTIES AND ABILITY TO AUGMENT HOST IMMUNE RESPONSES; HOWEVER, IFN RESPONSES CAN ALSO HAVE DETRIMENTAL OUTCOMES FOR THE HOST. THE FACTORS THAT DETERMINE THESE DIFFERENTIAL OUTCOMES ARE POORLY UNDERSTOOD. CHIKUNGUNYA VIRUS (CHIKV) IS A RE-EMERGING ALPHAVIRUS THAT CAUSES SEVERE, FEBRILE ARTHRITIS AND MYOSITIS. TYPE I IFNS ARE A KEY HOST RESPONSE DURING ALPHAVIRUS INFECTION. MICE LACKING THE TYPE I IFN RECEPTOR DEVELOP SEVERE AND RAPIDLY FATAL DISEASE FOLLOWING INFECTION WITH CHIKV OR OTHER ALPHAVIRUSES. IN STUDYING THIS RESPONSE, WE HAVE MADE SEVERAL INTERESTING OBSERVATIONS. FIRST, IFNS EXERT BOTH BENEFICIAL AND DETRIMENTAL EFFECTS DURING CHIKV INFECTION. SECOND, IFNS REGULATE THE HOST RESPONSE TO CHIVK BY SIGNALING ON NON-HEMATOPOIETIC CELLS, LIKELY STROMAL CELLS AND OTHER STRUCTURAL CELLS SUCH AS FIBROBLASTS AND ENDOTHELIAL CELLS. THE CONTRIBUTION OF STROMAL CELLS TO IN VIVO HOST IMMUNE RESPONSES REMAINS POORLY DEFINED, EVEN THOUGH THESE CELL TYPES ARE AMONG THE FIRST CELLS TO RESPOND TO VACCINATIONS AND VECTOR-BORNE INFECTIOUS DISEASES. OUR PROPOSED RESEARCH WILL TEST THE HYPOTHESIS THAT TYPE I IFNS PLAY DISTINCT ROLES THROUGHOUT THE COURSE OF CHIKV INFECTION DUE TO THE RESPONSES OF DISTINCT STROMAL CELL POPULATIONS. THE STUDIES PROPOSED WILL UTILIZE MOUSE GENETICS TO CONDITIONALLY DELETE IFN SIGNALING FROM DIFFERENT STROMAL CELLS, TEMPORAL ANTIBODY BLOCKING STRATEGIES, AND RNA SEQUENCING TECHNIQUES TO INTERROGATE HOW IFNS IMPACT THESE SPECIFIC CELLS AT DIFFERENT TIMES DURING CHIKV INFECTION. THESE FINDINGS HAVE THE POTENTIAL TO GREATLY EXPAND OUR UNDERSTANDING OF STROMAL CELLS IFN RESPONSES AND HOW THESE CELLS CONTRIBUTE TO SHAPING THE TISSUE-SPECIFIC IMMUNE RESPONSE DURING INFECTIONS AND VACCINATIONS.