Project 4: Structural Biology of Influenza Antibody-Antigen Interactions

项目4：流感抗体-抗原相互作用的结构生物学

• 批准号: 10549614
• 负责人: STEPHEN COPLAN HARRISON
• 金额: $ 31.86万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549614
• 关键词: 3-Dimensional; Acceleration; Affect; Affinity; Age; Antibodies; Antibody Affinity; Antigen-Antibody Complex; Antigens; Area; B cell repertoire; B-Lymphocytes; Binding; Cell Compartmentation; Collaborations; Compensation; Complex; Cryoelectron Microscopy; Directed Molecular Evolution; Epitope Mapping; Epitopes; Experimental Designs; Foundations; Goals; Hemagglutinin; Herd Immunity; Human; Immune; Immune response; Immunity; Immunization; Immunologics; Immunologist; In Vitro; Infection; Influenza; Influenza Hemagglutinin; Influenza vaccination; Laboratories; Maps; Memory B-Lymphocyte; Modeling; Molecular; Mus; Mutation; Neuraminidase; Outcome; Plasmablast; Reporting; Research; Resolution; Sampling; Serum; Specificity; Structure; Surface; T-Lymphocyte Epitopes; Vaccination; Vaccinee; Vaccines; Viral; Virus; Visualization; Work; age group; animation; arms race; cohort; design; experience; experimental study; future pandemic; human pathogen; immunogenicity; imprint; in vitro Model; influenza infection; influenza virus strain; insight; memory recognition; mouse model; movie; new technology; nonhuman primate; novel vaccines; pandemic virus; programs; response; structural biology; tool; vaccine response

Abstract Project 4 The goals of this component of a continuing Program Project are to advance understanding of the human humoral immune response to influenza virus infection and vaccination and to apply that understanding to immunogen design for next generation vaccines. To contribute to those goals, this Project has the following four Aims. (1) Analyze the distribution of neuraminidase (NA) epitopes recognized by memory B cells in recently vaccinated individuals, as a foundation both for analysis of the epitope- dependent response to NA and for design of immunogens in Project 3. (2) Carry out a broad analysis of the way in which the response to influenza vaccination depends on the age of the subjects and hence the extent of antigenic experience with influenza and the subtype responsible for immune imprinting. We will sample the accessible components of the human B-cell repertoire from several representatives of distinct age groups and map their epitopes by binding and, for representatives of all epitopic regions across the hemagglutinin molecule, by cryo-EM structure determination. This component will include influenza NA, but focus largely on hemagglutinin (HA). (3) Collaborate with Project 3 in three areas: studies of the influence of T-cell epitope diversity on humoral responses to designed HA immunogens, design of NA immunogens, and modeling the virus-antibody co-evolutionary "arms race" with directed evolution in the laboratory. (4) Determine structures of selected antibody:antigen complexes, to support efforts in Projects 1 and 2.

摘要项目4 持续计划项目的这一组成部分的目标是提高对 人类对流感病毒感染和疫苗接种的人体体液免疫反应，并应用 了解下一代疫苗的免疫原设计。为了为这些目标做出贡献 具有以下四个目标。 （1）分析由识别的神经氨酸酶（Na）表位的分布 最近接种疫苗个体的记忆B细胞，作为基础，既可以分析表位 - 对NA的依赖反应和项目3中的免疫原子的设计。（2）对 对流感疫苗接种的反应取决于受试者的年龄，因此 抗原经验的流感经验和负责免疫印迹的亚型。我们将 采样来自几位不同代表的人类B细胞曲目的可访问组成部分 年龄组并通过结合和对所有表现区域的代表来绘制其表位 血凝素分子，通过冷冻EM结构测定。该组成部分将包括甲型流感，但 主要专注于血凝素（HA）。 （3）与项目3合作在三个领域：研究 T细胞表位多样性对设计的HA免疫原子的体液反应，NA免疫原子的设计和 在实验室中，对病毒 - 抗体共同进化的“军备竞赛”进行建模。 （4） 确定选定抗体的结构：抗原复合物，以支持项目1和2中的努力。