Structural and Functional Studies of gp42 and HLA Class II in EBV Entry

EBV 进入中 gp42 和 HLA II 类的结构和功能研究

• 批准号: 7795184
• 负责人: Theodore S Jardetzky
• 金额: $ 41.17万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-22 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795184
• 关键词: Address; Affect; African Burkitt' s lymphoma; Antibodies; Area; Award; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Biology; Biophysics; Budgets; Burkitt Lymphoma; C-terminal; Cell fusion; Cell membrane; Cells; Child; Complement 3d Receptors; Complement Receptor; Complex; Critiques; Data; Detection; Development; Disease; Dissection; EBV-associated disease; Environment; Epithelial; Epithelial Cells; Epstein-Barr Virus Infections; Evaluation; Family; Funding; Glycoproteins; HLA Antigens; Hairy Leukoplakia; Hematopoietic; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; In Vitro; Individual; Kinetics; Knowledge; Large-Cell Immunoblastic Lymphoma; Lead; Ligands; Light; Lymphoproliferative Disorders; MHC Class I Genes; Malignant Neoplasms; Maps; Mediating; Medical; Membrane; Membrane Fusion; Molecular; Mutate; Mutation; Myomatous neoplasm; N-terminal; Nasopharyngeal Undifferentiated Carcinoma; Paramyxovirus; Pathology; Peptides; Postdoctoral Fellow; Process; Protein Binding; Proteins; Published Comment; Research; Research Personnel; Role; Signal Transduction; Site; Stomach Carcinoma; Structure; Students; Suggestion; T-Cell Lymphoma; Talents; Testing; Thermodynamics; Tissues; Training; Tropism; Validation; Viral; Viral Proteins; Virion; Virus; Virus Receptors; Virus-Induced Membrane Fusion; Western Blotting; base; combinatorial; crosslink; immunosuppressed; in vivo; insight; member; mutant; novel; novel therapeutics; pathogen; programs; public health relevance; receptor; receptor binding; research study; skills; therapeutic target; tissue tropism; virology

DESCRIPTION (provided by applicant): EBV is a causative agent in endemic Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma (NPC). EBV is also recognized as an important pathogen in immunosuppressed individuals, causing a variety of proliferative disorders including immunoblastic lymphomas, oral hairy leukoplakia, and an unusual tumor of muscle origin in immunosuppressed children. EBV is also a factor in a variety of other human malignancies including some T-cell lymphomas, Hodgkin lymphoma, Burkitt's lymphoma, and gastric carcinoma. The pathologies suggest a wide variety of tissue tropism for EBV in vivo. In vitro and in vivo, the cells that are most susceptible to EBV infection and permissive for viral replication are of B cell origin. The major viral envelope glycoprotein 350 (gp350) binds to the complement receptor type two (CD21) that is abundantly expressed on B cells. Fusion of the virion membrane with the cell membrane minimally requires a complex of viral proteins that includes gB, gH, gL, and gp42. gp42 has been specifically found to bind to human leukocyte antigen (HLA) class II and this interaction is required for EBV entry into B lymphocytes. To date, little is known about the mechanism that EBV uses to bind and penetrate B cells. This proposal will analyze the role of gp42 and its interaction with HLA for viral entry by structure-function studies. Clarifying the interactions between cellular receptors and viral glycoproteins is essential for understanding the tropisms behind EBV associated diseases. PUBLIC HEALTH RELEVANCE: This proposed research represents a collaborative research program between Dr. Longnecker and Dr. Jardetzky to define the molecular mechanisms involved in Epstein-Barr virus (EBV) entry into B lymphocytes, the major target cell of EBV in human hosts. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases and the proposed research may result in the identification of new therapeutics for EBV infections as well as the herpesvirus family in general of which EBV is a member.

描述（由申请人提供）：EBV 是地方性伯基特淋巴瘤和未分化鼻咽癌 (NPC) 的病原体。 EBV 也被认为是免疫抑制个体的重要病原体，在免疫抑制儿童中引起多种增殖性疾病，包括免疫母细胞淋巴瘤、口腔毛状白斑和一种不寻常的肌肉来源肿瘤。 EBV 也是多种其他人类恶性肿瘤的一个因素，包括一些 T 细胞淋巴瘤、霍奇金淋巴瘤、伯基特淋巴瘤和胃癌。病理学表明 EBV 在体内具有多种组织趋向性。在体外和体内，最容易受到 EBV 感染并允许病毒复制的细胞是 B 细胞来源的。主要病毒包膜糖蛋白 350 (gp350) 与 B 细胞上大量表达的补体受体二型 (CD21) 结合。病毒体膜与细胞膜的融合至少需要病毒蛋白复合物，其中包括 gB、gH、gL 和 gp42。已明确发现 gp42 与 II 类人类白细胞抗原 (HLA) 结合，这种相互作用是 EBV 进入 B 淋巴细胞所必需的。迄今为止，人们对 EBV 结合和渗透 B 细胞的机制知之甚少。该提案将通过结构功能研究来分析 gp42 的作用及其与 HLA 的相互作用，以促进病毒进入。阐明细胞受体和病毒糖蛋白之间的相互作用对于理解 EBV 相关疾病背后的趋向性至关重要。 公共健康相关性：这项拟议的研究代表了 Longnecker 博士和 Jardetzky 博士之间的一项合作研究计划，旨在定义 Epstein-Barr 病毒 (EBV) 进入 B 淋巴细胞（人类宿主中 EBV 的主要靶细胞）所涉及的分子机制。 EBV 与多种造血、上皮和淋巴增殖性疾病相关，拟议的研究可能会导致确定 EBV 感染以及 EBV 所属的疱疹病毒家族的新疗法。