The molecular basis of viral tolerance in bats

蝙蝠之所以能够成为人畜共患病病毒的天然宿主，归因于它们先天免疫系统的某些方面。特别是，蝙蝠对病原体的检测和反应似乎与人类不同，这使得它们能够耐受对其他哺乳动物有害的病毒。到目前为止，研究已经确定了导致蝙蝠免疫和炎症反应受抑的几个谱系特有的机制；然而，这些机制主要集中在少数假定的储藏物种及其近亲，约占蝙蝠物种的1%。因此，目前尚不清楚绝大多数蝙蝠物种(它们经历了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，这些机制是否会使它们容易受到病毒感染，并可能参与未来的人畜共患病。我们将通过筛选数百个物种的关键先天免疫基因，进行蝙蝠免疫适应的首次大规模比较研究，涵盖这一群体的全部进化和生态多样性。为了测试假定的分子适应(氨基酸变化)如何改变对病毒感染的免疫反应，我们将运行基于细胞的分析，重点研究代表天然免疫中不同效应途径的三种关键蛋白质(STING、NLRP3和MyD88)。最后，我们将研究在这些和其他基因座上存在的有影响力的分子适应是否可以解释蝙蝠病毒关联的已知变异。

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.