Defining the impact of complement inhibition by tick saliva in tick-borne virus evolution and adaptive immune responses in murine models of infection

Disease caused by tick-borne viruses (TBVs) has been increasing in incidence in the past decade, with few approved vaccines or therapeutics. Among these, the tick-borne flavivirus Powassan virus (POWV) is an RNA virus which frequently causes neuroinvasive disease in humans and transmitted by Ixodes ticks. These and other ticks are equipped with a unique store of salivary proteins that create an immunosuppressive environment enabling long-term attachment to a host during a bloodmeal. One aspect of host-TBV interactions that is not well understood is how the viral pathogens replicating in this niche may be afforded an advantage. This saliva activated transmission (SAT) is known to occur with POWV infection, but the underlying mechanisms behind it remain to be elucidated. This research proposed in this application will dissect how one important aspect of SGE immunosuppression-complement inhibition-impacts the development of the adaptive immune response in vaccinated and unvaccinated murine hosts, and how virus replication and subsequent dissemination to secondary sites of replication can drive TBV disease. In addition to existing expertise in TBVs and emerging infectious disease, our group has characterized the kinetics of viral replication and the development of POWV-specific B and T cell responses in murine models of infection. Furthermore, in conjunction with our collaborators, we have developed a virus-like particle (VLP) based vaccination strategy capable of protecting against lethal POWV challenge. How complement inhibition impacts the development of POWV-specific B and T cell responses in vaccinated and unvaccinated murine hosts is the subject of Aim 1. Aim 2 focuses on quantifying the impact of complement inhibition on neuropathological disease and virus evolution to drive disease in the murine host. The fellowship training plan described in this proposal is designed to address important gaps in the applicant's training prior to completion of her doctoral dissertation defense. These gaps will primarily be addressed by: 1) advancing the applicants repertoire of virology and immunology tools and high-impact publications, 2) allowing the applicant to acquire a new skillset analyzing next generation sequencing data, 3) encouraging the applicant's attendance at in-person meetings for purposes of networking and seeking a suitable postdoctoral mentor. The research and training goals set forth in this proposal will be accomplished in the environment of the sponsor and co-sponsors at Saint Louis University and Colorado State University in a highly collaborative and trainee focused setting.