Transmission dynamics and fitness of reemerging St. Louis encephalitis virus in mosquito vectors and West Nile virus naïve and immune avian reservoirs

/Abstract The flavivirus St. Louis encephalitis virus (SLEV) infects humans to cause febrile illness and rare fatal encephalitis. In California (CA), although human SLEV cases were detected from the 1940s-2003, none were reported from 2004-2015. Since 2015, SLEV reemerged and spread to cause more cases in CA and the Western US, including in areas with concurrent West Nile virus (WNV), a related flavivirus that invaded CA in 2003 that uses the same Culex vectors and avian hosts as SLEV. The reasons for the 11-year disappearance of SLEV from CA and its expansion since 2015 are unclear. Spread of WNV across the US was facilitated by augmented avian infection and enhanced vector competence but no studies have assessed host or vector phenotype for reemerging SLEV. Our genetic tracing studies show that post-2015 (contemporary) SLEV in the Western US likely originated in South America and is genetically distinct from pre-2003 (historic) SLEV. Our experimental studies show that birds inoculated with historic SLEV one month after WNV inoculation, a time when WNV neutralizing antibody titers are high, do not mount SLEV viremias, suggesting that SLEV after 2003 was displaced by extensive WNV avian herd immunity. Antibody-mediated neutralization is a hallmark of protection from flavivirus viremia and disease and antibody therapies are used in severe human cases of WNV and SLEV. Antibody is assumed to protect WNV immune birds from SLEV viremia and to prevent reinfection from sequential SLEV>SLEV infection but has never been experimentally confirmed. Our preliminary data show that serum from birds inoculated with historic WNV poorly neutralize some contemporary SLEV strains in vitro. Reduced antibody mediated cross-neutralization of contemporary SLEV by contemporary WNV could explain reemergence and persistence of SLEV in avian hosts. Augmented avian or mosquito infection may also contribute to SLEV spread. We observe increased infectivity of reemerging SLEV isolated in successive years since 2015 in duck embryonic fibroblast cells, but whether this pattern also manifests in avian reservoirs and in mosquito vectors is not known. To understand drivers of reemergence, the goal of this project is to identify how changing SLEV-vector-avian host interactions and cross-protection by WNV promote SLEV reemergence. This will be accomplished via 3 project Aims: 1) Determine transmission competence and fitness of contemporary versus historic SLEV in Culex, 2) Define avian fitness, antibody kinetics, and antibody-mediated protection for contemporary versus historic SLEV, and 3) Evaluate avian cross-protection conferred by prior WNV for contemporary versus historic SLEV. This project is significant in that it will define SLEV transmission dynamics in the context of sequential invasion and concurrent spread of 2 Culex-borne flaviviruses endemic to the US. Project Number: 1R01AI194449-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Lark Coffey (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA AT DAVIS, DAVIS, CA | Award Amount: $3,161,373 | Activity Code: R01 | Study Section: Transmission of Vector-Borne and Zoonotic Diseases Study Section [TVZ] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19444901