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: 8234940
• 负责人: Daved H. Fremont
• 金额: $ 32.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234940
• 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; Natural Immunity; 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; adaptive immunity; 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（IFN）活性在病毒感染的初始阶段就被排列起来，IFN介导 应答通过直接抑制病毒复制和间接抑制病毒复制， 刺激先天性和适应性免疫。毫不奇怪，IFN介导的信号传导是病毒感染的有利靶点。 托词在这项提议中，我们着手探索两种病毒的生物物理和功能属性， 编码诱饵受体，选择性地中和I型和III型IFN的生物效应。 鼠痘病毒编码一个诱饵受体，混杂地结合并阻断所有的抗病毒作用。 I型IFN以物种独立的方式表达，鼠IFN-β是显著的例外。Yaba类 疾病病毒编码一种相关的诱饵受体，该受体也能抑制灵长类动物的I型（α和β） 作为III型（λ）IFN。有趣的是，这些病毒蛋白质都没有任何重要的序列 与用于I型或III型IFN信号转导的不同受体组分相似。我们 提出的研究旨在剖析选择性诱饵受体介导的 使用不同的实验方法抑制IFN。在提案的目标1中，我们将确定 用X射线晶体学和定量分析病毒诱饵受体抑制IFN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一起使用 定向进化以开发具有独特细胞因子结合特性的变体诱饵受体。在目标2中， 将研究干扰素诱饵受体功能的细胞机制。痘病毒分泌的蛋白质 与细胞表面通过未知的受体相互作用，我们建议确定和调查。 我们还将研究是否有其他病毒编码干扰素诱饵。在目标3中，我们将探讨IFN的作用， 隔离的小鼠痘发病模型。将产生编码 选择性地抑制IFN-α、IFN-β或IFN-λ作用的新诱饵受体， 病毒感染，以便更好地了解这些细胞因子在抗病毒免疫中的具体作用。