Identification of bat antiviral innate immune effectors

Numerous recent disease outbreaks have been linked to zoonotic viruses originating from bats, including Marburg, Nipah, and the severe acute respiratory viruses like SARS-CoV-2. Countless virus-host encounters during bat evolution have shaped chiropteran immunity to balance defense and tolerance to viral infections, ultimately participating in bats current interplay with viruses and capacity as a viral reservoir. One of the first barriers against invading pathogens is the innate immunity, which notably includes antiviral factors that directly or indirectly inhibit the replication of invading viruses in the host cell. Recent research on bats showed the functional diversification of several antiviral effectors underscoring their pivotal role in bat immunity. However, because only a handful have been studied, my goal is to identify key and novel antiviral effectors within bat genomes, employing a bioinformatics-driven approach coupled with cellular and molecular virology techniques. First, I will perform genomic, transcriptomic and phylogenomic analyses to identify the genes expressed in immune pathways and under strong positive selection during bat evolution (denoting their in vivo importance). Second, I will characterize the most promising candidates, by genetic knockout and overexpression of variants in bat and human cell lines. Finally, the antiviral activity of the candidates will be tested against a broad spectrum of viruses: retroviruses, positive- and negative-strand RNA viruses. Taken together, the proposed project will not only identify novel antiviral factors in bats, which are also active in human cells, but will also shed light on the adaptive processes of chiropteran innate immunity, which occurred during bat evolution.