Viral evasion of IFN function by decoy receptor sequestration

病毒通过诱饵受体隔离来逃避干扰素功能

• 批准号: 7672148
• 负责人: Daved H. Fremont
• 金额: $ 32.54万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-09 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672148
• 关键词: Affinity; Antiviral Agents; Antiviral Response; Binding; Binding Proteins; Binding Sites; Biological; Biological Assay; Cell surface; Cloning; Complement; Complex; Cowpox; Crystallography; Docking; Ectromelia; Engineering; Goals; Host Defense; Human; IFNAR1 gene; IFNAR2 gene; Immunity; Infectious Ectromelia; Interferon-alpha; Interferon-beta; Interferons; Kinetics; Ligands; Marshal; Mediating; Methods; Modeling; Mouse Pox Virus; Mus; Pathogenesis; Play; Poxviridae; Primates; Property; Proteins; Proteomics; Reagent; Recombinants; Role; Signal Transduction; Site; Staging; Structure; Surface; Variant; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Yeasts; base; biodefense; cytokine; directed evolution; gain of function; infectious disease model; interest; novel; receptor; receptor function; research study; response

Interferon (IFN) activity is marshaled early against the initial stages of viral infection, and IFN mediated responses play an essential role in host defense by directly inhibiting viral replication and by indirectly stimulating innate and adaptive immunity. Not surprisingly, IFN mediated signaling is a favored target of viral subterfuge. In this proposal we set out to explore the biophysical and functional attributes of two virally encoded decoy receptors that selectively neutralize the biological effects of type-l and type-Ill IFNs. Ectromelia virus encodes a decoy receptor that promiscuously binds and blocks the antiviral effects of all type-l IFNs in a species independent manner, with the notable exception of murine IFN-beta. The Yaba-like disease virus encodes a related decoy receptor that capably inhibits primate type-l (alpha and beta) as well as type-Ill (lamda) IFNs. Interestingly, neither of these viral proteins shares any significant sequence similarity with the distinct receptor components used for type-l or type-Ill IFN signal transduction. Our proposed studies aim to dissect the mechanism and consequences of selective decoy receptor mediated IFN inhibition using a diverse arsenal of experimental methods. In Aim 1 of the proposal we will determine the structural basis of IFN inhibition by viral decoy receptors using x-ray crystallography and quantitative protein interaction analysis. Results from these studies will be used in concert with yeast surface display directed evolution to develop variant decoy receptors with unique cytokine binding properties. In Aim 2 we will examine the cellular mechanisms of IFN decoy receptor function. The secreted poxvirus proteins tightly associate with cell surfaces through an unknown receptor interaction we propose to identify and investigate. We will also examine whether additional viruses encode IFN decoys. In Aim 3 we will explore the role of IFN sequestration in the mousepox pathogenesis model. Ectromelia recombinants will be generated that encode novel decoy receptors that selectively inhibit the actions of IFN-alpha, IFN-beta, or IFN-lambda at sites of viral infection in order to better understand the specific roles of these cytokines in anti-viral immunity.

干扰素(干扰素)的活性是针对病毒感染的初始阶段进行早期调度的，并且干扰素介导 应答通过直接抑制病毒复制和间接抑制病毒复制在宿主防御中发挥重要作用 刺激先天免疫和获得性免疫。毫不奇怪，干扰素介导的信号转导是病毒的首选靶点。 诡计。在这项建议中，我们开始探索两种病毒的生物物理和功能属性 编码的诱骗受体，选择性中和L和III型干扰素的生物效应。 蜕皮病病毒编码一种诱骗受体，它混杂地结合并阻断所有病毒的抗病毒作用 L型干扰素以一种独立于物种的方式表达，但小鼠干扰素-β除外。类似亚巴的人 疾病病毒编码一种相关的诱骗受体，能够抑制灵长类动物L(阿尔法和贝塔) 作为类型Ill(Lamda)IFN。有趣的是，这两种病毒蛋白都没有相同的重要序列。 与L或III型干扰素信号转导所用的不同受体成分相似。我们的 拟议的研究旨在剖析选择性诱骗受体介导的机制和后果 抑制干扰素的实验方法多种多样。在提案的目标1中，我们将确定 用X射线结晶学和定量方法研究病毒诱骗受体抑制干扰素的结构基础 蛋白质相互作用分析。这些研究的结果将与酵母表面展示相结合使用 定向进化以开发具有独特细胞因子结合特性的不同诱饵受体。在《目标2》中，我们 将研究干扰素诱骗受体功能的细胞机制。紧密分泌的痘病毒蛋白 通过一种未知的受体相互作用与细胞表面结合，我们建议对其进行鉴定和研究。 我们还将检查是否有其他病毒编码干扰素诱饵。在目标3中，我们将探索干扰素的作用 鼠痘发病模型中的隔离。将产生编码外膜蛋白的重组子 新型诱骗受体选择性抑制干扰素-α、干扰素-β或干扰素-lambda的作用 以更好地了解这些细胞因子在抗病毒免疫中的具体作用。