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

• 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
• 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

 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（由申请方提供）：人巨细胞病毒（HCMV，一种疱疹病毒）可引起终身、持续/潜伏感染，在健康人群中大部分无症状，但如果宿主免疫力幼稚或受损，则可诱发严重疾病。HCMV编码>170种病毒蛋白，其中超过一半的蛋白具有调节宿主先天性和适应性免疫防御的功能。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对于促进疫苗和抗病毒药物开发至关重要。NK细胞在控制病毒感染中是至关重要的，并且HCMV已经进化出几种抑制NK细胞活化的机制。在这项提案中，我们将研究基因产物UL 141，编码的强毒株的HCMV，我们假设已经发展到调节免疫信号网络，通过靶向两个配体的NK细胞受体，以及TNF死亡受体。UL 141抑制TRAIL-DR以及NK细胞活化配体CD 155的表达。与HCMV基因产物US 2一起，UL 141还下调NK细胞活化受体DNAM-1的第二配体CD 112。此外，我们推测UL 141模拟TIGIT的功能，TIGIT是一种也抑制NK细胞活化的免疫受体。揭示UL 141如何与由IG和TNF家族蛋白组成的信号网络发生串扰，将产生关于这些非经典结合相互作用如何调节宿主免疫的有价值的信息。