Consequences of IFIT Gene Evolution on Species-Specific Antiviral Immunity

 描述(申请人提供)：一些最致命的人类病毒感染是由其他物种的人畜共患病造成的。这使得确定定义人类对目前在其他物种中传播的病毒的易感性的宿主因素成为努力的重要部分 预防和治愈人畜共患传染病。已知的限制跨物种传播的宿主因素是哺乳动物基因组中一些进化最快的因素，通常是由于与病毒的进化“军备竞赛”造成的。我的研究重点是使用这些基因适应的进化特征来发现和表征先天免疫的新机制，并确定宿主免疫中的遗传变异如何影响病毒传播。我的建议集中在IFIT(干扰素诱导的四肽重复)基因家族，这是一些对病毒感染反应最高上调的基因。我发现IFIT也是哺乳动物进化最快的基因之一，这让我假设，IFIT基因库和序列的物种间差异将影响病毒在物种之间的传播成功。我的实验室将使用一种整合了生物化学、进化遗传学和病毒学见解的多学科方法来测试这些假设。在目标1中，我们将研究Ifit1的序列进化和由于基因的获得和丢失如何影响不同宿主可以限制的病毒。在目标2中，我将确定人类Ifit1如何发挥作用来限制病毒复制。这些研究不仅将阐明IFIT进化的机制后果，而且还将确定先天抗病毒免疫的物种特异性变化。最后，更广泛地说，我的研究将强调使用进化引导的方法来发现和表征对跨物种病毒传播重要的因素的力量。

 DESCRIPTION (provided by applicant): Some of the most deadly human viral infections are the result of zoonoses from other species. This makes identification of host factors that define human susceptibility to viruses currently circulating in other species an essential part of efforts to prevent and cure zoonotic infections. Host factors known to restrict cross-species transmission are some of the most rapidly evolving factors in mammalian genomes, often as a result of evolutionary 'arms races' with viruses. My research focuses uses these evolutionary signatures of gene adaptation to discover and characterize new mechanisms of innate immunity and determine how genetic variation in host immunity impacts viral transmission. My proposal focuses on the IFIT (Interferon-induced with tetratricopeptide repeat) gene family, some of the most highly upregulated genes in response to viral infection. I have found that IFITs are also among the most rapidly evolving genes in mammals, leading me to hypothesize that inter-species difference in IFIT gene repertoire and sequence will influence the success of viral transmission between species. My lab will test these hypotheses using a multidisciplinary approach that integrates insights from biochemistry, evolutionary genetics, and virology. In Aim 1, we will examine how IFIT1 evolution, both in sequence and due to gene gain and loss, influences the viruses that different hosts can restrict. In Aim 2, I will determine how a human IFIT1 functions to restrict viral replication. These studies will not only shed light on the mechanistic consequences of IFIT evolution, but will also identify species-specific changes in innate antiviral immunity. Finally, more broadly, my research will highlight the power of using an evolution-guided approach to discover and characterize factors important for cross-species viral transmission.