Project Grant F32AI186477

TRANSMISSION DYNAMICS AND FITNESS OF REEMERGING ST. LOUIS ENCEPHALITIS VIRUS IN MOSQUITO VECTORS AND WEST NILE VIRUS NATIVE AND IMMUNE AVIAN RESERVOIRS - PROJECT SUMMARY/ABSTRACT: ST. LOUIS ENCEPHALITIS VIRUS (SLEV) IS A MOSQUITO-BORNE FLAVIVIRUS THAT CAUSES FEBRILE ILLNESS AND RARE FATAL ENCEPHALITIS IN HUMANS. SLEV BECAME ENDEMIC IN CALIFORNIA (CA) IN THE 1940'S, BUT BETWEEN 2003 AND 2014, NO HUMAN CASES NOR MOSQUITO ISOLATIONS WERE RECORDED IN CA, DEMONSTRATING AN SLEV REGIONAL EXTINCTION. IN 2003, A CLOSELY RELATED FLAVIVIRUS, WEST NILE VIRUS (WNV), ENTERED CA AND OTHER WESTERN STATES LEADING TO 7,597 CASES IN HUMANS (2003-2022) AND FATAL NEUROLOGIC DISEASE IN HORSES AND WILD BIRDS. LATER IN 2015, CONTEMPORARY SLEV STRAINS (CSLEV) TRACED TO SOUTH AMERICA EMERGED IN THE WESTERN US AND HAS SINCE BEEN DETECTED IN HUMANS AND CULEX MOSQUITOES THROUGHOUT CA IN EVERY SUBSEQUENT YEAR DESPITE CONTINUED WNV PRESENCE. THE REASONS FOR THE 11-YEAR HIATUS OF HISTORICAL SLEV STRAINS (HSLEV) FROM CA AND CSLEV EXPANSION SINCE 2015 REMAINS UNCHARACTERIZED. OUR EXPERIMENTAL STUDIES SHOW THAT HOUSE SPARROWS (PASSER DOMESTICUS), A KNOWN AVIAN RESERVOIR HOST SPECIES FOR WNV AND SLEV, WILL NOT MOUNT HSLEV VIREMIA AFTER DEVELOPING NEUTRALIZING ANTIBODIES FOR WNV, SUGGESTING THAT HSLEV WAS DISPLACED PRIMARILY BY WNV AVIAN HERD IMMUNITY. ADDITIONALLY, OUR PRELIMINARY DATA SHOW THAT SERUM FROM BIRDS INOCULATED WITH WNV POORLY NEUTRALIZE CSLEV STRAINS IN VITRO. GIVEN THESE FINDINGS, OUR CENTRAL HYPOTHESIS FOR THIS PROPOSAL IS THAT HSLEV STRAINS WERE LIKELY "OUT-COMPETED" IN AVIAN RESERVOIR HOSTS BY CROSS- PROTECTIVE WNV DERIVED HUMORAL (ANTIBODY-MEDIATED) IMMUNITY, AND THAT CSLEV STRAINS ESCAPE WNV AVIAN HOST IMMUNITY SUCH THAT INFECTION WITH WNV DOES NOT CONFER CROSS-PROTECTION AGAINST CSLEV INFECTION. TO UNDERSTAND DRIVERS OF SLEV REEMERGENCE, THE GOAL OF THIS PROJECT IS TO IDENTIFY HOW CHANGING SLEV-VECTOR- AVIAN HOST INTERACTIONS AND CROSS-PROTECTION BY WNV PROMOTE SLEV REEMERGENCE. TO TEST OUR HYPOTHESIS, WE PROPOSE A SET OF EXPERIMENTS TO INVESTIGATE 1) TRANSMISSION COMPETENCE AND FITNESS OF CSLEV VERSUS HSLEV IN CULEX MOSQUITOES, AND 2) AVIAN FITNESS, ANTIBODY KINETICS, AND ANTIBODY-MEDIATED PROTECTION FOR AND BETWEEN CSLEV, HSLEV, AND WNV IN HOUSE SPARROWS. THE FIRST AIM WILL USE TWO PRIMARY VECTORS IN CA, CULEX QUINQUEFASCIATUS, AND TARSALIS FOR ASSESSING VIRAL TITERS IN TISSUES AND SALIVA, AND TIME TO DISSEMINATION AND TRANSMISSION IN MOSQUITOES THAT INGEST DIFFERENT DOSES OF SLEV-SPIKED BLOODMEALS. NEXT, MOSQUITOES WILL BE CHALLENGED VIA MIXED INFECTION WITH CONTEMPORARY SLEV AND AN INFECTIOUS CLONE COMPETITOR MADE FROM HISTORIC OR CONTEMPORARY SLEV TO ASSESS RELATIVE FITNESS. IN THE SECOND AIM, WE WILL INOCULATE WILD-CAUGHT HOUSE SPARROWS WITH WNV, CSLEV, AND HSLEV SERIALLY IN VARYING ORDERS OR CONCURRENTLY IN ORDER TO DETERMINE INTERVIRAL INFECTION KINETICS (VIREMIA AND ANTIBODY RESPONSES) AND HOST FITNESS. LASTLY, PASSIVE TRANSFER OF SLEV (CONTEMPORARY OR HISTORICAL) OR WNV ANTISERA FROM PREVIOUSLY INOCULATED BIRDS WILL BE GIVEN TO NAIVE SPARROWS WITH SUBSEQUENT CHALLENGE BY HETEROLOGOUS VIRUS. THE SIGNIFICANCE OF THIS PROPOSAL LIES IN ITS APPLICATION TO BETTER PREDICT AND MITIGATE FUTURE HUMAN EPIDEMICS FOR BOTH WNV AND SLEV.