Repertoire studies of human antibodies to RSV and MPV F

RSV 和 MPV F 人类抗体的谱研究

• 批准号: 10249184
• 负责人: Theodore S Jardetzky
• 金额: $ 62.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-06 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249184
• 关键词: Address; Animals; Antibodies; Antibody Response; Antibody-mediated protection; Antigenic Variation; Antigens; Antiviral Agents; B cell repertoire; B-Lymphocytes; Biochemical; Bronchiolitis; Child; Chimeric Proteins; Clinic Visits; Collaborations; Disease Outbreaks; Elderly; Engineering; Epidemiology; Epitope Mapping; Epitopes; Family; Frequencies; Health; Hospitalization; Human; Human Metapneumovirus; Immune response; Immune system; Immunity; Immunoglobulin A; Immunologics; Individual; Infant; Infection; Knowledge; Laboratories; Life; Maps; Medical; Modification; Molecular Conformation; Morbidity - disease rate; Mutate; Mutation; Palivizumab; Para-Influenza Virus Type 3; Paramyxovirus; Pneumonia; Pneumovirus; Population; Prophylactic treatment; Protein Conformation; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Sampling; Specificity; Structure; Subunit Vaccines; Universities; Vaccine Design; Vaccines; Variant; Viral; Virus; Visit; base; comparative; cross reactivity; high risk; human pathogen; influenzavirus; insight; member; murine monoclonal antibody; neutralizing antibody; novel; novel strategies; protein folding; recurrent infection; respiratory; respiratory virus; response; small molecule; tool; vaccine development; viral entry inhibitor

Project Summary In this project, the Jardetzky and Crowe laboratories will collaborate to investigate the neutralizing antibody response to respiratory syncytial virus (RSV) and human metapneumovirus (HMPV), using complementary structural, biochemical and immunological approaches. RSV and HMPV are respiratory viruses that cause widespread morbidity within the human population second only to influenza virus. RSV is the most common cause of bronchiolitis and pneumonia in infants worldwide. The virus also impacts the elderly and others with weakened immune systems. HMPV was identified in 2001 and has been causing respiratory illnesses in the human population for over 50 years. Similar to RSV, HMPV infections are associated with a significant burden of hospitalizations and clinic visits in young children and in the elderly. Despite limited antigenic variation, RSV and HMPV cause repeated infections throughout life and are associated with a lack of induction of durable immunity. A clear explanation for this ability of the viruses to reinfect previously exposed individuals is still lacking, although multiple hypotheses have been developed. The RSV and HMPV fusion (F) proteins are the major targets of neutralizing antibodies (nAbs), and nAbs targeting the prefusion conformation of the RSV F protein have been shown to be the most potent inhibitors of viral entry. However, our understanding of the antibody response to HMPV is much more limited. In this proposal, the Jardetzky and Crowe laboratories will address outstanding issues in RSV and HMPV antibody immunity by studying monoclonal and repertoire- based B cell responses to both viruses, conducting functional and structural mapping of antibody epitopes and studying the sequence determinants of HMPV F conformational stabilization. !

项目摘要 在这个项目中，Jardetzky和Crowe实验室将合作研究中和抗体 对呼吸道合胞病毒（RSV）和人偏肺病毒（HMPV）的反应，使用互补的 结构、生物化学和免疫学方法。RSV和HMPV是呼吸道病毒， 在人群中的广泛发病率仅次于流感病毒。RSV是最常见的 细支气管炎和肺炎的病因。该病毒还影响老年人和其他患有 削弱免疫系统。HMPV于2001年被发现，并已导致呼吸道疾病， 人口超过50年。与RSV相似，HMPV感染与显著的负担相关 儿童和老年人的住院率和门诊率。尽管抗原变异有限，但RSV HMPV和HMPV在一生中引起反复感染，并与缺乏持久性免疫缺陷的诱导有关。 免疫力对于这种病毒能够再次感染先前接触过的个体的能力， 虽然有很多假设，但缺乏。RSV和HMPV融合（F）蛋白是RSV和HMPV的融合蛋白。 中和抗体（nAb）的主要靶标，以及靶向RSV F融合前构象的nAb 蛋白质已被证明是病毒进入的最有效的抑制剂。然而，我们对 对HMPV的抗体应答则有限得多。在这项提案中，Jardetzky和Crowe实验室将 通过研究单克隆抗体和抗体库，解决RSV和HMPV抗体免疫中的突出问题- 基于对两种病毒的B细胞应答，进行抗体表位的功能和结构作图， 研究HMPV F构象稳定性的序列决定因素。 !