Project 4: Structural Biology of Influenza Antibody-Antigen Interactions

摘要项目4 持续计划项目的这一部分的目标是促进对 人类对流感病毒感染和疫苗接种的体液免疫应答及其应用 了解下一代疫苗的免疫原设计。为了实现这些目标，本项目 有以下四个目标。(1)分析识别的神经氨酸酶(NA)表位的分布 最近接种疫苗的个体的记忆B细胞，作为分析表位的基础- 对NA的依赖反应和项目3中免疫原的设计。(2)对 接种流感疫苗的反应取决于受试者的年龄，因此 流感和免疫印记亚型的抗原性经验的程度。我们会 从几个不同的代表中采样人类B细胞谱系的可访问成分 年龄组，并通过结合映射其表位，以及，对于整个 血凝素分子，通过冷冻-EM结构测定。这一组成部分将包括甲型流感，但 主要关注血凝素(HA)。(3)在三个方面与项目3合作：研究 设计的HA免疫原的体液反应的T细胞表位多样性，NA免疫原的设计，以及 在实验室中用定向进化模拟病毒-抗体共同进化的“军备竞赛”。(4) 确定选定抗体的结构：抗原复合体，以支持项目1和2的努力。

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.