Immunological findings of West Caucasian bat virus in an accidental host

The Lyssavirus genus includes seventeen viral species able to cause rabies, an acute and almost invariably fatal encephalomyelitis of mammals. Rabies virus (RABV), which represents the type species of the genus, is a multi-host pathogen that over the years has undergone multiple events of host-switching, thus occupying several geographical and ecological niches. In contrast, non-RABV lyssaviruses are mainly confined within a single natural host with rare spillover events. In this scenario, unveiling the mechanisms underlying the host immune response against a virus is crucial to understand the dynamics of infection and to predict the probability of colonization/adaptation to a new target species. Presently, the host response to lyssaviruses has only been partially explored, with the majority of data extrapolated from RABV infection. West Caucasian bat virus (WCBV), a divergent lyssavirus, has recently been associated with a spillover event to a domestic cat, raising concern about the risks to public health due to the circulation of the virus in its natural host. Through this study we have investigated the immune response determined by the WCBV versus two widely known lyssaviruses. We selected the Syrian hamster as representative of an accidental host, and chose the intramuscular route in order to mimic the natural infection. In hamsters, WCBV was highly pathogenic, determining 100% lethality and mild encephalitis. In comparison with Duvenhage virus (DUVV) and RABV, we found that WCBV displayed an intermediate ability to promote cellular antiviral response, produce pro-inflammatory cytokines, and recruit and activate lymphocytes in the hamsters' central nervous system.

Although all lyssaviruses cause fatal encephalomyelitis in mammals, they display a different host tropism and pathogenicity, with the ecology of Rabies virus (RABV) continually evolving and adapting to new host species. In 2020, West Caucasian bat virus (WCBV) was identified as the causative agent of rabies in a domestic cat in Italy. This event raised concerns about its public health consequences, due to the absence of biologicals against the infection. Our study investigates the host immune response triggered by WCBV in comparison with a pathogenic strain of RABV and the low pathogenic Duvenhage lyssavirus (DUVV), as a proxy to understand the mechanisms leading to lyssavirus spillover and pathogenicity. We overall confirm that previous evidence indicating an inverse relationship between lyssavirus pathogenicity and immune response is applicable for WCBV as well. Importantly, this work represents the first transcriptomic analysis of the WCBV interaction in the central nervous system with an accidental host.