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

• 批准号: 8996707
• 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
• 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/8996707
• 关键词: Address; Adenovirus E3 19K Protein; Adenovirus Infections; Adenovirus Protein; Adenoviruses; Affinity; Antigen Presentation; Antigen Presentation Pathway; Antiviral Agents; Binding; Binding Proteins; Biochemical; Biological Assay; Biology; Cell Line; Cell Surface Proteins; Cell surface; Cells; Cellular Immunity; 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; Health; Histocompatibility Antigens Class I; Human; 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; 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; adaptive immunity; base; calreticulin; cell killing; clinically relevant; design; immunoregulation; insight; interest; killer inhibitory receptor; killings; mutant; pathogen; pediatric patients; receptor; reticulum cell; small molecule; tapasin; three dimensional structure; viral detection; virus pathogenesis

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）：新生的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，最终导致内源性和病毒肽的细胞表面表现为细胞毒性T-cells（CTLS）。这一途径在控制病毒感染中的重要性是由病毒发展为干扰MHC I成熟并抑制抗原表现的许多策略的事实强调的。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。因为持续性病毒是临床上相关的病原体，所以我们必须了解它们如何通过人类免疫系统逃避检测。这些知识与理解宿主 - 病原体相互作用有关，它还告诉我们I类抗原表现途径对病毒干扰的敏感性。我们利用这些信息的能力可以使抗病毒药物的开发受益。 人类腺病毒（ADS）引起的疾病范围从胃肠道和呼吸道感染到眼部感染。 AD编码与感染细胞的ER内结合并保留MHC I类分子的E3-19K蛋白。结果表明，E3-19K降低了感染细胞上MHC I表达的水平，这种作用可保护被感染的细胞免受CTL裂解。我们有兴趣研究E3-19K多年来E3-19K逃避免疫监测的分子机制。我们最近对E3-19K功能进行了许多关键观察。我们表明，AD血清型2（AD2）E3-19K与未成熟（无肽）和成熟（充满肽的）MHC I分子的关联。我们还表明，E3-19K靶向HLA-A和-b基因座的MHC I分子，但不是HLA-C和-e基因座的分子。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AD2 E3-19K与HLA-A2结合。迄今为止，E3-19K免疫调节功能的许多重要方面尚未完全理解。不知道E3-19K是否利用多种策略来干扰ER内MHC I成熟（AIM＃1）；还不知道哪些MHC I分子在感染细胞上被E3-19K特别下调（AIM＃2）；还没有人研究了E3-19K/MHC I自然杀手功能协会的作用（AIM＃2）；而且，我们仍然缺乏对E3-19K/MHC I协会中高亲和力和相互作用特异性的结构基础的理解（AIM＃3）。该项目的目的是基于我们以前的贡献，并以系统的方式解决这些显着问题。 我们研究的重要性是由I类抗原途径在消除入侵病原体，我们的AD2 E3-19K/HLA-A2结构的新颖性中发挥的关键作用，以及AD感染对儿童和免疫能力敏感的患者的知识。我们预计，完成研究后，我们将对E3-19K如何抵消MHC I限制的细胞免疫防御措施并影响AD感染过程。