Structural basis of UL141 mediated NK cell inhibition by HCMV

HCMV 介导的 UL141 介导的 NK 细胞抑制的结构基础

基本信息

批准号：
8873656
负责人：
Dirk M Zajonc
金额：
$ 26.55万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8873656
关键词：
Affinity Antiviral Agents Antiviral Response Apoptosis Binding Biochemical C-terminal CD94 Antigen Cell surface Cells Cessation of life Complex Cytomegalovirus Cytomegalovirus Infections Data Dimerization Disease Down-Regulation Engineering Equilibrium Evolution Family Herpesviridae Host Defense Human Human cytomegalovirus US2 protein ITIM Immune Immune response Immune system Immunity Immunoglobulin Domain Immunoglobulins Immunologic Receptors Individual Infection Kinetics Lead Letters Ligands Light Mediating Molecular NK Cell Activation Natural Killer Cells Pathway interactions Persons Proteins Recombinants Signal Transduction Solutions Specificity Structure Substrate Specificity Surface Surface Plasmon Resonance T-Lymphocyte TNF-related apoptosis-inducing ligand Testing Therapeutic Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vaccines Viral Viral Proteins Virulent Virus Virus Diseases Work X-Ray Crystallography base design drug development immunoglobulin receptor inhibitor/antagonist insight latent persistent infection monomer nectin poliovirus receptor prevent protein function public health relevance receptor receptor binding three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV, a ß-herpesvirus) causes lifelong, persistent/latent infection that is largely asymptomatic in healthy persons, but can induce serious disease if host immunity is naïve or compromised. HCMV encodes for >170 viral proteins, more than half which function to modulate host innate and adaptive immune defenses. Characterizing the structural and molecular basis of the interactions that occur between these HCMV and host proteins is crucial to facilitate vaccine and antiviral drug development. NK cells are crucial in controlling viral infection and HCMV has evolved several mechanisms to inhibit NK cell activation. In this proposal we will study the gene product UL141, encoded by virulent strains of HCMV, that we hypothesize has evolved to modulate immune signaling networks by targeting both ligands for NK cell receptors, as well as the TNF death receptors. UL141 inhibits expression of TRAIL-DR as well as CD155, an NK cell activating ligand. Together with HCMV gene product US2, UL141 also downregulates CD112, a second ligand for the NK cell activating receptor DNAM-1. In addition, we speculate that UL141 mimics the function of TIGIT, an immunoreceptor that also inhibits NK cell activation. Uncovering how UL141 crosstalks with signaling networks comprised of Ig and TNF family proteins will yield valuable information regarding how these non-canonical binding interactions function to regulate host immunity.

描述（由申请人提供）：人类巨细胞病毒（HCMV，一种 ß-疱疹病毒）会导致终生、持续/潜伏感染，在健康人中基本上无症状，但如果宿主免疫力未成熟或受损，则可诱发严重疾病（HCMV 编码>170）。病毒蛋白，超过一半的功能是调节宿主先天性和适应性免疫防御，表征这些 HCMV 和宿主蛋白之间发生的相互作用的结构和分子基础。 NK 细胞对于控制病毒感染至关重要，并且 HCMV 已进化出多种抑制 NK 细胞激活的机制。在本提案中，我们将研究由 HCMV 毒株编码的基因产物 UL141。 UL141 已进化为通过靶向 NK 细胞受体的配体来调节免疫信号网络，并且 UL141 抑制 TRAIL-DR 和 CD155 的表达。与 HCMV 基因产物 US2 一起，UL141 还下调 NK 细胞激活受体 DNAM-1 的第二种配体 CD112。此外，我们推测 UL141 模仿了 TIGIT（一种也抑制 NK 细胞的免疫受体）。揭示 UL141 如何与由 Ig 和 TNF 家族蛋白组成的信号网络相互作用，将产生有关这些蛋白如何被激活的有价值的信息。非规范结合相互作用可调节宿主免疫。