Pathogen-driven evolution of innate antiviral defense mechanisms

项目摘要 传染病是全球卫生的巨大负担。然而，我们对许多 宿主进化以防御病原体的机制，以及病原体反进化以 打败这些防御。重要的是，这些宿主-病原体进化冲突的结果（即， 宿主或病原体是否成功）最终决定了我们对感染的易感性。因此， 最重要的是，我们解决以下问题：什么是关键的基因和机制， 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 变异影响感染的易感性？我们的研究带来了一个进化导向的视角来回答 利用病原体和它们的宿主的利益必然不一致这一事实， 彼此之间。也就是说，如果宿主成功抵御了病原体，就存在进化压力 来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个成功的 感染，宿主被迫适应。这些来回的动态推动了双方的不断创新 宿主-病原体分子相互作用的两个方面，导致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质已经被驱动到 通过与病原体的遗传冲突迅速进化，实际上允许病原体引导我们找到宿主基因， 对健康最重要的机制和途径。基于这种进化导向的方法，我们的 目前的工作集中在几个不完全理解的转录后和后， 宿主抗病毒防御中的翻译调节机制。目前的一个重点领域是调查 抗病毒机制和动态进化的基因家族的进化结果，称为 IFIT，基于mRNA修饰区分宿主和病毒mRNA。另一个目的是确定 免疫功能的一个不明确的特点，但迅速演变的基因家族，称为PARP，催化 翻译后添加ADP-核糖到蛋白质中。使用不同的病毒学模型，加上遗传学， 和生物化学方法，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易感性的影响，同时也揭示了mRNA在更广泛的机制中的作用。 修饰和ADP-核糖基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，以确定其他快速发展，但研究不足的调控机制，我们 假设是人对病毒感染易感性的另外决定因素。我们的总体使命 我们的工作是利用这种进化引导的方法来提供独特的见解宿主防御机制， 病原体免疫逃避，病原体复制的物种特异性屏障，以及病原体驱动的 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.