Poxviral antagonism of the IFIT-mediated antiviral response

描述(申请人提供)：许多干扰素刺激基因(ISGs)和其他抗病毒机制保护人类免受各种病毒的侵袭。从病毒的角度来看，许多ISG是病毒复制的强大障碍。因此，为了在进化上取得成功，病毒必须找到方法来逃避这些宿主的抗病毒机制。事实上，多种病毒编码特定的因子，使它们能够直接对抗宿主的抗病毒蛋白。因此，此类病毒拮抗剂的鉴定和表征对于了解人类对病毒的易感性和设计新的治疗方法和疫苗具有很高的相关性。尽管病毒在生物医学上具有重要意义，但识别新的病毒拮抗剂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的功能研究表明，宿主基因的已知病毒拮抗通常与该宿主基因的快速适应性进化或正选择相关。本申请旨在极大地扩展这一概念的用途，提出正选择分析可用于预测未知病毒拮抗剂针对哪些宿主抗病毒蛋白，并能够识别先前未知的拮抗剂。我们将专注于IFIT(干扰素诱导的四肽重复)基因家族，这是一组高度干扰素诱导的广泛作用的抗病毒因子，对宿主防御多种病毒非常重要。IFit基因没有已知的病毒拮抗剂。然而，它们中的一些是在强烈的正选择下进化的，这让我们假设病毒反复以拮抗剂为靶标。我们将结合从进化遗传学中收集的见解，以及生物化学和病毒学技术，测试IFIT蛋白是否是病毒拮抗的直接目标。这些研究将确定IFIT蛋白和病毒拮抗剂之间的生化和功能相互作用，并测试IFIT拮抗剂对病毒复制的重要性。其他实验将检查IFIT进化的功能后果，以及这是否定义了IFIT蛋白对当前流行病毒拮抗的敏感性。最后，实验进化将揭示病毒对抗IFIT介导的宿主防御所采取的进化路径。这些研究不仅将阐明拮抗剂在病毒逃避IFIT介导的抗病毒反应中所起的作用，而且也将代表一种潜在的广泛适用的策略，用于重要抗病毒基因的病毒拮抗剂的鉴定和表征。 公共卫生相关性：为了成功地进行感染，病毒需要克服广泛的宿主抗病毒防御。通过调查病毒经常攻击的宿主防御系统，我们可以深入了解最关键的抗病毒防御系统以及病毒用来逃避它们的方法。这些研究不仅将更好地了解这些关键的免疫系统功能和人类对流行病毒的易感性，还可能为开发新的抗病毒疗法提供有效的靶点。

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.