Subversion of MHC class I antigen presentation by viral immunomodulatory proteins

病毒免疫调节蛋白颠覆 MHC I 类抗原呈递

基本信息

批准号：
8723605
负责人：
MARLENE BOUVIER
金额：
$ 39.88万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723605
关键词：
Address Adenovirus E3 19K Protein Adenovirus Infections Adenovirus Protein Adenoviruses Affinity Antigen Presentation Antigen Presentation Pathway Antiviral Agents Binding Biochemical Biological Assay Biology Cell Line Cell Surface Proteins Cell surface Cells Cellular Immunity Child Chimera organism Complex Crystallography Cytolysis Cytotoxic T-Lymphocytes Data Detection Development Disease Down-Regulation ERp57 Educational process of instructing Effector Cell Endoplasmic Reticulum Eye Infections Gastrointestinal tract structure Goals HLA-A gene HLA-A2 Antigen HLA-C Antigens Histocompatibility Antigens Class I Human Human Adenoviruses Human Cell Line Immune Immune response Immune system Immunocompromised Host Immunoglobulins Immunologic Surveillance Individual Invaded KLRD1 gene Knowledge Life Major Histocompatibility Complex Mediating Molecular Natural Killer Cells Pathway interactions Peptides Pharmaceutical Preparations Play Predisposition Process Protein Binding Proteins Respiratory Tract Infections Role Serotyping Site Specificity Staging Structure Surface System Testing Time Translating Viral Viral Interference Viral Proteins Virus Virus Diseases YARS gene base calreticulin cell killing clinically relevant design immunoregulation insight interest killer inhibitory receptor killings mutant pathogen public health relevance receptor reticulum cell small molecule tapasin three dimensional structure viral detection virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Nascent major histocompatibility complex (MHC) class I molecules undergo a stringent maturation process within the endoplasmic reticulum (ER) of cells, culminating in the cell-surface presentation of endogenous and viral peptides to cytotoxic T-cells (CTLs). The importance of this pathway in controlling viral infections is underlined by the fact that viruses have evolved numerous strategies to interfere with MHC I maturation and suppress antigen presentation. It is thought that these strategies enable viruses to persist in infected host cells. Because persistent viruses are clinically relevant pathogens, itis essential that we understand how they evade detection by the human immune system. This knowledge is relevant for understanding host-pathogen interaction, and it also informs us on the susceptibility of the class I antigen presentation pathway to viral interferences. Our ability to harness this information can benefit the development of antiviral drugs. Human Adenoviruses (Ads) cause diseases ranging from gastrointestinal and respiratory tract infections to eye infections. Ad encodes the E3-19K protein that binds to and retains MHC class I molecules within the ER of infected cells. It was shown that E3-19K reduces levels of MHC I expression on infected cells, an effect that protects infected cells from lysis by CTLs. We have been interested in studying the molecular mechanism by which E3-19K evades immune surveillance for many years. We have recently made a number of key observations on E3-19K function. We showed that Ad serotype 2 (Ad2) E3-19K associates with immature (peptide-free) and mature (peptide-filled) MHC I molecules. We also showed that E3-19K targets MHC I molecules of the HLA-A and -B loci but not those of the HLA-C and -E loci. Importantly, we determined the first three-dimensional structure of an E3-19K/MHC I complex, namely Ad2 E3-19K bound to HLA-A2, by x-ray crystallography. To date, many important aspects of the immunomodulatory function of E3-19K remains incompletely understood. It is not known if E3-19K utilizes more than one strategy to interfere with MHC I maturation within the ER (Aim #1); it is also not known which MHC I molecules are specifically downregulated by E3-19K on infected cells (Aim #2); no one has yet examined the role of the E3-19K/MHC I association on natural killer functions (Aim #2); and we still lack an understanding of the structural basis for high affinity and specificity of interaction in the E3-19K/MHC I association (Aim #3). The goal of this project is to build on our previous contributions and address these salient questions in a systematic manner. The significance of our studies is highlighted by the critical role that the class I antigen presentatin pathway plays in eliminating invading pathogens, the novelty of our Ad2 E3-19K/HLA-A2 structure, and the knowledge that Ad infections can be fatal in children and immunocompromised patients. We expect that upon completing our studies, we will have a more in depth understanding of how E3-19K counteracts MHC I- restricted cellular immune defenses and influences the course of Ad infection.

描述（由申请人提供）：新生主要组织相容性复合物（MHC）I类分子在细胞内质网（ER）内经历严格的成熟过程，最终将内源性和病毒肽呈递到细胞毒性T细胞的细胞表面（ CTL）。病毒已进化出多种策略来干扰 MHC I 成熟和抑制抗原呈递，这一事实强调了该途径在控制病毒感染中的重要性。人们认为这些策略使病毒能够在受感染的宿主细胞中持续存在。由于持久性病毒是临床相关的病原体，因此我们必须了解它们如何逃避人类免疫系统的检测。这些知识与理解宿主-病原体相互作用相关，并且还告诉我们 I 类抗原呈递途径对病毒干扰的敏感性。我们利用这些信息的能力可以有利于抗病毒药物的开发。人类腺病毒 (Ads) 会引起胃肠道、呼吸道感染和眼部感染等多种疾病。 Ad 编码 E3-19K 蛋白，该蛋白与受感染细胞内质网内的 MHC I 类分子结合并保留。结果表明，E3-19K 降低受感染细胞上 MHC I 表达水平，这种作用可以保护受感染细胞免遭 CTL 裂解。多年来我们一直对研究E3-19K逃避免疫监视的分子机制感兴趣。我们最近对 E3-19K 功能进行了一些关键观察。我们发现 Ad 血清型 2 (Ad2) E3-19K 与未成熟（无肽）和成熟（充满肽）MHC I 分子相关。我们还表明，E3-19K 靶向 HLA-A 和 -B 基因座的 MHC I 分子，但不靶向 HLA-C 和 -E 基因座的 MHC I 分子。重要的是，我们通过 X 射线晶体学确定了 E3-19K/MHC I 复合物的第一个三维结构，即与 HLA-A2 结合的 Ad2 E3-19K。迄今为止，E3-19K 免疫调节功能的许多重要方面仍未完全了解。目前尚不清楚 E3-19K 是否利用不止一种策略来干扰 ER 内 MHC I 的成熟（目标#1）；也不知道受感染细胞上的 E3-19K 会特异性下调哪些 MHC I 分子（目标#2）；尚未有人研究过 E3-19K/MHC I 关联在自然杀伤功能中的作用（目标#2）；我们仍然缺乏对 E3-19K/MHC I 关联中高亲和力和特异性相互作用的结构基础的了解（目标#3）。该项目的目标是在我们之前的贡献的基础上，系统地解决这些突出问题。 I 类抗原呈递蛋白途径在消除入侵病原体中发挥的关键作用、Ad2 E3-19K/HLA-A2 结构的新颖性以及 Ad 感染对儿童和儿童可能致命的认识凸显了我们研究的重要性。免疫功能低下的患者。我们期望在完成我们的研究后，我们将更深入地了解 E3-19K 如何对抗 MHC I 限制性细胞免疫防御并影响 Ad 感染的过程。