Repertoire studies of human antibodies to RSV and MPV F

RSV 和 MPV F 人类抗体的谱研究

基本信息

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
项目类别：
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

项目摘要

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实验室将合作调查中和抗体使用互补的反应呼吸综合病毒（RSV）和人元病毒（HMPV）结构，生化和免疫学方法。 RSV和HMPV是引起呼吸道病毒人口中广泛的发病率仅次于流感病毒。 RSV是最常见的全世界婴儿的细支气管炎和肺炎的原因。该病毒还通过免疫系统减弱。 HMPV于2001年确定，一直在引起呼吸系统疾病人口超过50年。与RSV相似，HMPV感染与重大负担有关幼儿和老年人的住院和诊所就诊。尽管抗原变异有限，但RSV HMPV在一生中引起重复感染，并且与缺乏耐久的诱导有关免疫。关于病毒恢复以前暴露个体的这种能力的明确解释仍然是缺乏，尽管已经提出了多个假设。 RSV和HMPV融合（F）蛋白是中和抗体（NABS）的主要靶标和靶向RSV F构象的NABS 蛋白质已被证明是病毒进入的最有效抑制剂。但是，我们对对HMPV的抗体反应更加有限。在这个建议中，Jardetzky和Crowe实验室将通过研究单克隆和曲目 - 基于B细胞对两种病毒的反应，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。呢