Bat lyssavirus pathogenesis and entry mechanisms

About This Grant

Project Summary Lyssaviruses which include rabies virus circulate in multiple bat and mammalian species resulting in approximately 60,000 independent spillover events into people each year. Nearly all cases of rabies virus infection in humans are lethal without vaccination or post-exposure prophylaxis. Rabies virus typically transmits from the saliva of an infected animal after a bite where it replicates locally in skeletal muscle before infecting peripheral motor neurons and then the central nervous system, causing lethal encephalitis. At least seven of the 21 known lyssaviruses have caused lethal disease in people. The case fatality rates of these bat lyssaviruses are variable, highlighting distinct and important differences in susceptibility and pathogenesis of these viruses with rabies virus. Despite the pathogenic and zoonotic potential of this virus family, it is unknown which of these pre-emergent bat lyssaviruses can infect human cells, how they enter cells, which cell types they infect, and whether they can cause central nervous system infection and encephalitis. Our preliminary data reveal that representative bat lyssaviruses from all three major phylogroups can infect human cell lines and brain organoids. Importantly, these viruses show variable susceptibility to rabies vaccine sera highlighting that existing vaccines and post-exposure prophylaxis may be inadequate to confer protection from bat lyssaviruses. We also conducted genome wide CRISPR screens to identify novel bat lyssavirus entry factors. This revealed a novel host factor that was essential for entry of all tested bat lyssaviruses. Despite the genetic similarity of these viruses, they have distinct geographical range, reservoir hosts, vaccine susceptibility, and pathogenic potential. Here we will leverage our expertise in viral pathogenesis and human organoids to systematically uncover how these viruses enter cells, what cells these viruses infect, and whether these viruses are poised to cause severe disease in people. Aim 1 will determine the cell tropism, pathogenesis, and vaccine susceptibility of bat lyssaviruses. Aim 2 will investigate the role of both described and novel entry factors in bat lyssavirus infection and pathogenesis using human organoids and animal models. Collectively, this will enable risk stratification of pre-emergent bat lyssaviruses to improve surveillance, and aid development of vaccines and therapeutics for this wide-spread and poorly studied emerging virus family known to cause lethal disease in humans.