The molecular basis of viral tolerance in bats

蝙蝠作为人畜共患病毒天然宿主的能力归因于其先天免疫系统的某些方面。特别是，与人类相比，蝙蝠对病原体的检测和反应似乎不同，这使它们能够容忍对其他哺乳动物有害的病毒。迄今为止的研究已经确定了蝙蝠免疫和炎症反应减弱的几种谱系特异性机制；然而，这些研究主要集中在少数假定的宿主物种及其近缘种，约占蝙蝠物种的1%。因此，目前尚不清楚绝大多数蝙蝠物种（跨越6000万年的进化）是否也具有耐受病毒的免疫机制，如果是的话，这些机制是否可能使它们易受病毒感染，并可能参与未来的人畜共患病溢出。我们将通过筛选数百个物种的关键先天免疫基因，跨越这一群体的完整进化和生态多样性，对蝙蝠免疫适应性进行首次大规模比较研究。为了测试假设的分子适应（氨基酸改变）如何改变对病毒感染的免疫反应，我们将进行基于细胞的检测，重点关注代表先天免疫中不同效应途径的3个关键蛋白（STING， NLRP3和MyD88）。最后，我们将研究这些和其他基因座中存在的有效分子适应是否可以解释已知的蝙蝠-病毒关联变异。

The ability of bats to act as natural reservoir hosts of zoonotic viruses has been attributed to 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 mammals. 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 bat species. It is therefore not known whether the vast majority of bat species (which span >60 million years of evolution) also possess immune mechanisms for tolerating viruses, and, if so, whether these might predispose them to viral infections and potential involvement in future zoonotic spillovers. We will conduct the first large-scale comparative study of bat immune adaptations by screening key innate immunity genes across hundreds of species, spanning this group's full evolutionary and ecological diversity. To test how putative molecular adaptations (amino acid changes) alter immune responses to viral infection, we will run cell-based assays, focusing on 3 key proteins (STING, NLRP3 and MyD88) that represent different effector pathways in innate immunity. Finally, we will examine whether the presence of impactful molecular adaptations in these and other loci can explain known variation in bat-virus associations.