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，贾德茨基实验室和克劳实验室将合作研究中和抗体 对呼吸道合胞病毒(RSV)和人类偏肺病毒(HMPV)的应答 结构、生化和免疫学方法。RSV和HMPV是引起 在人类人口中广泛流行的发病率仅次于流感病毒。呼吸道合胞病毒是最常见的 全世界婴儿毛细支气管炎和肺炎的原因。该病毒还影响老年人和其他患有 免疫系统减弱。HMPV于2001年被发现，一直在引起呼吸道疾病 人类人口已经超过50年了。与RSV相似，HMPV感染与沉重的负担有关 儿童和老年人的住院和就诊情况。尽管抗原变异有限，但RSV 和HMPV会在一生中反复感染，并与缺乏耐受性诱导有关 豁免权。对于这种病毒再次感染先前接触过的人的能力，一个明确的解释仍然是 尽管已经提出了多种假说，但仍然缺乏。RSV和HMPV融合(F)蛋白是 中和抗体的主要靶点(NAB)，以及针对RSV F的预融合构象的NAB 蛋白质已被证明是最有效的病毒进入抑制剂。然而，我们对 对HMPV的抗体反应要有限得多。在这项提案中，贾德茨基和克劳实验室将 通过研究单抗和谱系来解决RSV和HMPV抗体免疫中的突出问题 基于B细胞对这两种病毒的反应，进行抗体表位的功能和结构映射以及 研究HMPV F构象稳定的序列决定因素。 好了！