Pathogen-driven evolution of innate antiviral defense mechanisms

项目总结 传染病是全球卫生的巨大负担。然而，我们只是很难理解许多 宿主进化来防御病原体的机制，以及病原体已经反进化到 击败这些防御。重要的是，这些宿主-病原体进化冲突的结果(即 宿主或病原体是成功的)最终决定我们对感染的敏感性。因此，它是 最重要的是，我们要解决以下问题：什么是关键基因和机制 保护我们免受感染，病原体如何抵消这些防御，以及宿主基因如何 变异会影响感染的易感性吗？我们的研究带来了进化导向的观点来回答 这些问题是利用病原体和它们的宿主的利益必然是不一致的这一事实来提出的 彼此之间的关系。也就是说，如果宿主成功防御了病原体，就存在进化压力。 以进化出一种克服这种防御的方法。同样，如果病原体建立了一种成功的 感染，宿主被迫适应。这些往返的动力推动了双方不断的创新 寄主-病原体分子相互作用的侧面，导致了我们看到的广泛的遗传和功能多样性 今天。我们的研究明确地利用这种多样性来发现哪些宿主蛋白被驱动到 通过与病原体的遗传冲突而快速进化，实际上允许病原体引导我们找到宿主基因， 对健身最重要的机制和途径。基于这种以进化为导向的方法，我们的 目前的工作集中在几个不完全了解的转录后和后转录后的重要性。 宿主抗病毒防御中的翻译调控机制。目前的一个重点领域是调查 一个动态进化的基因家族的抗病毒机制和进化结果，称为 IFITs，根据信使核糖核酸的修饰区分宿主和病毒的mRNAs。另一个目标是确定 一种特性不佳但进化迅速的基因家族的免疫功能，称为PALP，它催化 ADP-核糖在蛋白质中的翻译后加成。使用不同的病毒学模型，再加上基因 和生化方法，这些研究的目的不仅是确定IFIT和PARP的后果 基因进化对病毒感染的易感性，但也揭示了mRNA的更广泛的机制作用 修饰和ADP核糖化在宿主抗病毒防御和细胞调节中的作用。最后，我们正在开发 全基因组工具来识别其他快速进化但未被研究的调控机制，我们 假设是人类对病毒感染易感性的额外决定因素。我们的总体使命是 工作是使用这种进化引导的方法来提供对宿主防御和 病原体免疫逃避，病原体复制的物种特定障碍，以及病原体驱动的进化 细胞功能。

PROJECT SUMMARY Infectious diseases are an enormous burden on global health. However, we only poorly understand the many mechanisms that hosts have evolved to defend against pathogens and that pathogens have counter-evolved to defeat those defenses. Importantly, the result of these host-pathogen evolutionary conflicts (i.e. whether the host or the pathogen is successful) ultimately determine our susceptibility to infection. It is therefore of paramount importance that we address the following questions: what are the critical genes and mechanisms that protect us from infection, how do pathogens counteract those defenses, and how does host genetic variation affect susceptibility to infection? Our research brings an evolution-guided perspective to answering these questions by exploiting the fact that the interests of pathogens and their hosts are necessarily at odds with one another. That is, if the host successfully defends against a pathogen, there is evolutionary pressure on the pathogen to evolve a way to overcome that defense. Likewise, if the pathogen establishes a successful infection, the host is pressured to adapt. These back and forth dynamics drive constant innovation on both sides of host-pathogen molecular interactions, resulting in the wide genetic and functional diversity we see today. Our research explicitly leverages this diversity to discover which host proteins have been driven to rapidly evolve by genetic conflicts with pathogens, in effect allowing pathogens to lead us to the host genes, mechanisms and pathways that are most important for fitness. Based on this evolution-guided approach, our current work focuses on the importance of several incompletely understood post-transcriptional and post- translational regulatory mechanisms in host antiviral defense. One current area of focus is investigating the antiviral mechanisms and evolutionary consequences of a dynamically evolving family of genes, known as IFITs, that distinguish host from viral mRNAs based on mRNA modifications. Another aim is to determine the immune functions of a poorly characterized but rapidly evolving family of genes known as PARPs that catalyze the post-translational addition of ADP-ribose to proteins. Using diverse virology models, coupled with genetic and biochemical approaches, these studies aim to not only determine the consequences of IFIT and PARP gene evolution on susceptibility to viral infection, but also to reveal the broader mechanistic roles for mRNA modifications and ADP-ribosylation in host antiviral defense and cellular regulation. Finally, we are developing genome wide tools to identify other rapidly evolving but understudied regulatory mechanisms that we hypothesize are additional determinants of human susceptibility to viral infection. The overall mission of our work is to use this evolution-guided approach to provide unique insights into mechanisms of host defense and pathogen immune evasion, species-specific barriers to pathogen replication, and pathogen-driven evolution of cellular functions.