Poxviral antagonism of the IFIT-mediated antiviral response

描述（由申请人提供）：许多干扰素刺激基因（ISG）和其他抗病毒机制保护人类免受各种病毒的侵害。从病毒的角度来看，许多ISG代表了病毒复制的有效屏障。因此，为了在进化上取得成功，病毒必须找到逃避这些宿主抗病毒机制的方法。事实上，多种病毒编码特定的因子，使它们能够直接拮抗宿主的抗病毒蛋白。因此，这种病毒拮抗剂的鉴定和表征对于理解人类对病毒的易感性和设计新的疗法和疫苗是高度相关的。尽管有这种巨大的生物医学重要性，但识别新的病毒拮抗剂或甚至哪些宿主基因被病毒拮抗一直是困难的。我们以前的进化导向功能研究表明，已知的病毒对宿主基因的拮抗作用通常与该宿主基因的快速适应性进化或正选择相关。本申请试图通过提出阳性选择分析可用于预测未知病毒拮抗剂靶向哪些宿主抗病毒蛋白并能够鉴定先前未知的拮抗剂来极大地扩展该概念的实用性。我们将集中在IFIT（干扰素诱导的tetratricopeptide repeat）基因家族，一个高度干扰素诱导的广泛作用的抗病毒因子，对宿主防御几种病毒是重要的。IFIT基因没有已知的病毒拮抗剂。然而，它们中的一些已经在强阳性选择下进化，导致我们假设病毒用拮抗剂重复靶向它们。我们将测试IFIT蛋白是否是病毒拮抗作用的直接靶点，方法是结合从进化遗传学中收集到的见解，以及生物化学和病毒学技术。这些研究将定义IFIT蛋白和病毒拮抗剂之间的生物化学和功能相互作用，并测试IFIT拮抗作用对病毒复制的重要性。额外的实验将检查IFIT进化的功能后果，以及这是否定义了IFIT蛋白对目前流行的病毒的拮抗作用的敏感性。最后，实验进化将揭示病毒对抗IFIT介导的宿主防御的进化路径。这些研究不仅将阐明拮抗剂在病毒逃避IFIT介导的抗病毒应答中的作用，而且还将代表用于重新鉴定和表征重要抗病毒基因的病毒拮抗剂的潜在广泛适用的策略。 公共卫生相关性：为了成功感染，病毒需要克服一系列宿主的抗病毒防御。通过研究病毒经常针对的宿主防御，我们可以深入了解最关键的抗病毒防御以及病毒用来逃避它们的手段。这些研究不仅可以更好地了解这些关键的免疫系统功能和人类对循环病毒的易感性，还可以为开发新的抗病毒治疗提供有效的靶点。

DESCRIPTION (provided by applicant): Many interferon-stimulated genes (ISGs) and other antiviral mechanisms protect humans from a large variety of viruses. Taken from a viral perspective, many ISGs represent potent barriers to viral replication. Therefore, to be evolutionarily successful, viruses must find ways to evade these host antiviral mechanisms. Indeed, multiple viruses encode specific factors that allow them to directly antagonize host antiviral proteins. The identification and characterization of such viral antagonists is thus highl relevant for understanding human susceptibility to viruses and designing new therapies and vaccines. Despite this great biomedical importance, identifying novel viral antagonists or even which host genes are antagonized by viruses has been difficult. Our previous evolution-guided functional studies have revealed that known viral antagonism of a host gene is often correlated with rapid adaptive evolution, or positive selection, in that host gene. This application seeks to greatly expand the utility of this concept by proposing that positive selection analyses can be used to predict which host antiviral proteins are targeted by unknown viral antagonists and enable identification of the previously unknown antagonists. We will focus on the IFIT (Interferon-induced with tetratricopeptide repeat) gene family, a highly interferon-induced set of broadly-acting antiviral factors that are important for host defense against several viruses. IFIT genes have no known viral antagonists. However several of them have evolved under strong positive selection, leading us to hypothesize that viruses have repeated targeted them with antagonists. We will test whether IFIT proteins are direct targets of viral antagonism by employing a combination of insights gleaned from evolutionary genetics, together with biochemistry and virology techniques. These studies will define the biochemical and functional interactions between IFIT proteins and viral antagonists and test the importance of IFIT antagonism for viral replication. Additional experiments will examine the functional consequences of IFIT evolution, and whether this defines the susceptibility of IFIT proteins to antagonism by currently circulating viruses. Finally, experimental evolution will reveal the evolutionary path that viruses take to counteract IFIT-mediated host defenses. These studies will not only shed light on the role that antagonists play in viral evasion of the IFIT- mediated antiviral response, but will also represent a potentially widely applicable strategy for the de nov identification and characterization of viral antagonists of important antiviral genes. PUBLIC HEALTH RELEVANCE: To mount a successful infection, viruses need to overcome a wide array of host antiviral defenses. By investigating the host defenses that are frequently targeted by viruses, we can gain significant insight into the most critical antiviral defenses and the means that viruses use to evade them. These studies will not only provide a greater understanding of these crucial immune system functions and human susceptibility to circulating viruses, but may also suggest productive targets for development of new antiviral therapeutics.