BAT lyssavirus pathogenesis and entry mechanisms

The National Institute of Allergy and Infectious Diseases awarded Yale University $655,316 on July 9, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate bat lyssavirus pathogenesis and entry mechanisms.

The research addresses how lyssaviruses, including rabies virus, circulate in bat and mammalian species and spill over into humans at approximately 60,000 independent events annually. The project will systematically uncover how these viruses enter human cells, which cell types they infect, and whether they cause central nervous system infection and encephalitis. Preliminary data reveal that representative bat lyssaviruses from all three major phylogroups can infect human cell lines and brain organoids, and that these viruses show variable susceptibility to rabies vaccine sera, suggesting existing vaccines and post-exposure prophylaxis may be inadequate against bat lyssaviruses. The investigator team conducted genome-wide CRISPR screens identifying a novel host factor essential for entry of all tested bat lyssaviruses. Despite genetic similarity among these viruses, they exhibit distinct geographical range, reservoir hosts, vaccine susceptibility, and pathogenic potential. The work will leverage expertise in viral pathogenesis and human organoid models to map virus entry factors and susceptibility across lyssavirus phylogroups.

Performance occurs in New Haven, Connecticut. The period of performance runs from July 9, 2026, through June 30, 2031. This is a Project Grant, the standard assistance type for investigator-initiated research under NIAID's competitive grants program.

Abstract

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.