Project 4: Structural Biology of Influenza Antibody-Antigen Interactions

抽象项目4 持续性计划项目的这一组成部分的目标是促进对 人对流感病毒感染和疫苗接种体液免疫应答， 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)分析神经氨酸酶（NA）表位的分布， 最近接种疫苗的个体中的记忆B细胞，作为分析表位- NA依赖性应答和项目3中免疫原的设计。(2)广泛分析 对流感疫苗接种的反应取决于受试者的年龄， 流感的抗原经验的程度和负责免疫印记的亚型。我们将 从几个不同的代表中抽取人类B细胞库的可接近组分， 年龄组，并通过结合绘制其表位图，对于跨年龄组的所有表位区域的代表， 血凝素分子，冷冻电镜结构测定。这一部分将包括流感NA，但 主要集中在血凝素（HA）。(3)与项目3在三个领域开展合作： T细胞表位多样性对所设计的HA免疫原的体液应答、NA免疫原的设计以及 在实验室中用定向进化模拟病毒-抗体协同进化的“军备竞赛”。（四） 确定选定的抗体：抗原复合物的结构，以支持项目1和2的工作。

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.