The molecular basis of viral tolerance in bats

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The ability of bats to act as natural reservoir hosts of zoonotic viruses has been attributed to derived aspects of their innate immune systems. In particular, bats appear to detect and respond to pathogens differently compared to humans, allowing them to tolerate viruses that are harmful to other species. Studies to date have identified several lineage-specific mechanisms responsible for dampened immune and inflammatory responses in bats; however, these have mainly focused on a few putative reservoir species and their relatives, representing ~1% of extant bat species diversity. We will conduct the first large-scale study of bat immune adaptations by screening >150 genes in 300 species from across the bat clade, spanning >60 million years of evolution. We will apply sequence capture to obtain orthologues, and perform analyses of selection, parallelism and functional impact to identify compelling putative molecular adaptations. To assess the impact of lineage-specific putative adaptations on immune responses, we will then conduct functional assays on bat and human cells exposed to viruses. For this we will focus on the proteins STING, NLRP3 and MyD88 (which encompass central effector pathways for activating IFN, inflammasome and NFkB, respectively), in each case using CRISPR/Cas9 to build transgenic cell lines that differ with respect to key residues. Finally, we will examine whether the presence of impactful molecular adaptations in these and other loci can explain known variation in bat-virus interactions.



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