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，但如果宿主免疫力是幼稚的或受损的，则可能诱发严重的疾病。 HCMV 编码超过 170 种病毒蛋白，其中一半以上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的开发至关重要。 NK 细胞对于控制病毒感染至关重要，HCMV 已进化出多种机制来抑制 NK 细胞激活。在本提案中，我们将研究由 HCMV 强毒株编码的基因产物 UL141，我们假设该基因产物已经进化到通过靶向 NK 细胞受体配体以及 TNF 死亡受体来调节免疫信号网络。 UL141 抑制 TRAIL-DR 以及 NK 细胞激活配体 CD155 的表达。与 HCMV 基因产物 US2 一起，UL141 还下调 CD112（NK 细胞激活受体 DNAM-1 的第二个配体）。此外，我们推测 UL141 模仿了 TIGIT 的功能，TIGIT 是一种也抑制 NK 细胞激活的免疫受体。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，将产生有关这些非规范结合相互作用如何发挥调节宿主免疫功能的有价值的信息。