Project Grant F32AI200437

ELUCIDATING VIRAL AND HOST FACTORS THAT DRIVE CHIKUNGUNYA VIRUS NEUROVIRULENCE AND NEUROPATHOGENESIS USING MICE MODELS - PROJECT SUMMARY THE ALPHAVIRUS CHIKUNGUNYA VIRUS (CHIKV) PRESENTS A RE-EMERGING PUBLIC HEALTH THREAT AS THE GEOGRAPHIC RANGES OF MOSQUITO VECTORS EXPAND. LARGE-SCALE OUTBREAKS HAVE OCCURRED ACROSS INDIA, CHINA, AND THE AMERICAS, INCLUDING LOCAL TRANSMISSION IN TEXAS AND FLORIDA. CHIKV TYPICALLY INDUCES ARTHRITOGENIC DISEASE, BUT UP TO 25% OF CASES RESULT IN NEUROLOGICAL DISEASE, SUCH AS ENCEPHALITIS. WHILE THE FDA RECENTLY APPROVED A CHIKV VACCINE, TREATMENT FOLLOWING INFECTION IS STILL LIMITED TO SYMPTOMATIC CARE. A SIGNIFICANT CHALLENGE FOR DEVELOPING TREATMENTS PATIENTS DEVELOP NEUROLOGICAL SYMPTOMS AFTER VIRUS IS CLEARED. THE IMMUNE RESPONSE, PARTICULARLY T CELLS, HAS BEEN SHOWN TO MEDIATE DEVELOPMENT OF JOINT PATHOLOGY IN CHIKV PATIENTS. THEREFORE, HOST-DIRECTED THERAPIES THAT TARGET THE IMMUNE RESPONSE, WHETHER ALONE OR IN COMBINATION WITH ANTIVIRALS, REPRESENT PROMISING APPROACHES FOR COMBATTING CHIKV-INDUCED DISEASE. THEREFORE, AN UNDERSTANDING OF HOW HOST AND VIRAL FACTORS CONTRIBUTE TO CHIKV-INDUCED NEUROLOGICAL DISEASE IS CRITICAL FOR DEVELOPING EFFECTIVE COUNTERMEASURES. OUTBREAKS CAUSED BY CERTAIN CHIKV STRAINS ARE ASSOCIATED WITH HIGHER RATES OF NEUROLOGICAL DISEASE THAN OTHERS, SUGGESTING THAT VIRAL FACTORS CONTRIBUTE TO CHIKV NEUROPATHOGENESIS. HOWEVER, CLINICAL FEATURES OF NEUROLOGICAL CHIKV INFECTION VARY BY OUTBREAK AND GEOGRAPHICAL REGION, SUGGESTING HOST FACTORS PLAY A ROLE IN CHIKV ENCEPHALITIS. THE OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THE VIRAL AND HOST FACTORS THAT MEDIATE CHIKV- INDUCED NEUROLOGICAL DISEASE. THE LIMITED ACCESSIBILITY AND MINIMALLY REGENERATIVE NATURE OF THE CENTRAL NERVOUS SYSTEM (CNS) CREATE AN INSURMOUNTABLE BARRIER TO STUDYING THE COURSE OF NEUROLOGICAL CHIKV INFECTION IN HUMANS AND REQUIRE THE USE OF ANIMAL MODELS. MICE HAVE BEEN USED EXTENSIVELY TO STUDY ARTHRITOGENIC DISEASE INDUCED BY CHIKV AND NEUROLOGICAL DISEASE CAUSED BY OTHER ALPHAVIRUSES, INCLUDING LONG-TERM NEUROLOGICAL SEQUELAE. HOWEVER, ALMOST ALL MOUSE STUDIES EXAMINING NEUROLOGICAL CHIKV INFECTION HAVE UTILIZED NEONATAL OR IMMUNOCOMPROMISED MICE, WHICH DO NOT ACCURATELY REFLECT THE NEURODEVELOPMENTAL OR IMMUNOLOGICAL STATUS OF SUSCEPTIBLE HUMAN POPULATIONS. OUR LAB'S PRELIMINARY STUDIES HAVE SHOWN THAT YOUNG ADULT C57BL/6J MICE ARE SUSCEPTIBLE TO INFECTION, BUT DEVELOP MILD, NON-LETHAL CHIKV-INDUCED DISEASE WHEN INFECTED INTRACRANIALLY (IC) WITH SL15649. IN CONTRAST, IC SL15649-INFECTED CC041 MICE, A COLLABORATIVE CROSS STRAIN, DEVELOP BRAIN MODERATE TO SEVERE, LETHAL DISEASE. IN AIM 1, I WILL USE RECOMBINANT CHIKV VIRUSES TO INVESTIGATE WHAT VIRAL PROTEIN(S) ARE DRIVING NEUROINVASION AND NEUROVIRULENCE. IN AIM 2, I WILL USE B6 AND CC041 MICE TO DISSECT IMMUNE COMPONENTS THAT CONTRIBUTE TO CHIKV-INDUCED PATHOLOGY. TOGETHER, THESE DATA WILL HELP UNCOVER THE MECHANISMS THAT DRIVE CHIKV NEUROPATHOGENESIS, AND THE SKILLS AND TECHNIQUES GAINED THROUGH THIS PROJECT WILL PROVIDE ME WITH THE FOUNDATION NEEDED TO ESTABLISH MY INDEPENDENT RESEARCH PROGRAM FOCUSED ON HOST-PATHOGEN INTERACTIONS AND DEVELOPING THERAPEUTICS.