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部分的目标是增进对 人体对流感病毒感染和疫苗接种的体液免疫反应及其应用 了解下一代疫苗的免疫原设计。为了实现这些目标，该项目 有以下四个目标。 (1)分析神经氨酸酶(NA)识别的表位分布 最近接种疫苗的个体中的记忆 B 细胞，作为表位分析的基础 对 NA 的依赖反应以及项目 3 中免疫原的设计。 (2) 对 对流感疫苗接种的反应取决于受试者的年龄，因此 流感抗原经历的程度以及负责免疫印记的亚型。我们将 从几个不同的代表中对人类 B 细胞库的可访问成分进行采样 年龄组并通过结合绘制其表位图，对于整个年龄组的所有表位区域的代表 血凝素分子，通过冷冻电镜结构测定。该组件将包括流感 NA，但是 主要关注血凝素（HA）。 （3）与项目3在三个方面进行合作：研究 T 细胞表位多样性对设计的 HA 免疫原、NA 免疫原的设计和体液反应的影响 在实验室中通过定向进化对病毒-抗体共同进化“军备竞赛”进行建模。 (4) 确定所选抗体：抗原复合物的结构，以支持项目 1 和 2 中的工作。