Protective humoral immunity to influenza infection

对流感感染的保护性体液免疫

• 批准号: 9196008
• 负责人: Nicole Baumgarth
• 金额: $ 48.52万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-09 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196008
• 关键词: Adjuvant; Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody-mediated protection; Antigens; Antiviral Agents; Appearance; Applications Grants; Area; Attention; B cell differentiation; B-Lymphocytes; Blast Cell; Cells; Complement; Defect; Development; Flow Cytometry; Gene Targeting; Hemagglutinin; Homo; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Idiotypes; Immunoglobulin M; Immunohistochemistry; Inactivated Vaccines; Infection; Influenza; Influenza A virus; Influenza Hemagglutinin; Intervention; Kinetics; Knowledge; Label; Life; Ligands; Lung; Lymphoid Tissue; Measures; Mediating; Modeling; Molecular Target; Mus; Outcome; Outcome Study; Plasma; Plasma Cells; Plasmablast; Puerto Rico; Receptor Signaling; S100A9 gene; Signal Pathway; Signal Transduction; Signaling Protein; Structure of germinal center of lymph node; Testing; Therapeutic; Vaccination; Vaccines; Viral Antibodies; Virus; Virus Diseases; antiviral immunity; design; influenza virus vaccine; influenzavirus; lymph nodes; migration; neutralizing antibody; pathogen; prophylactic; receptor; response; vaccine efficacy; vaccine-induced immunity

PROJECT SUMMARY The extrafollicular (EF) B cell response generates virus-specific IgM, IgG and IgA in the airway lumen and local lymph nodes as early as 72h after influenza virus infection, correlating temporally with virus clearance. EF responses are distinct in kinetics, function and signaling requirements from the slower germinal center responses. EF B cell responses habe been largely dismissed as significant in pathogen- induced immunity, as they are though to generate only short-lived plasma cells and low affinity antibodies. Yet, consistent with recent studies on a requirement for high-affinity interaction between BCR and antigen for induction of EF responses, our studies show that a prototypic EF response to HA of influenza A/Puerto Rico /8/34 generates high-affinity protective antibodies long-term after influenza infection. Thus, identifying this response as a crucial component of primary influenza-infection-induced antiviral immunity. However, immunization with inactivated virus in adjuvant failed to induce EF responses, yet did induce strong germinal centers, thereby identifying a specific deficit in vaccine-induced humoral immunity, that may reduce its efficacy. Because the signals inducing EF responses are unknown, and their protective capacity is unclear, they cannot be exploited for therapeutic or prophylactic uses. To overcome this knowledge gap we propose to test our hypothesis that innate B cell direct signaling drives high affinity long-term protective antiviral humoral immunity via induction of strong EF responses. Specific Aim #1 will use gene-targeted mice to identify the receptors and signaling pathways responsible for EF development after influenza infection and complement inactivated influenza vaccines with their corresponding ligands to generate EF responses. Aim 2 will delineate the molecular targets of these signaling pathways for the differentiation of B cells to EF plasma blasts, following the fate of influenza HA-specific B cells. Aim 3 will assess the quality and protective capacity of EF and GC B cell responses. Successful outcome of these studies will provide a conceptual advance by demonstrating that EF responses to infection can generate high-affinity antibody responses and provide immune protection. Identification of the ligands, signaling pathways and the gene targets that drive EF responses will increase fundamental knowledge on the mechanisms of B cell differentiation and open the door for the exploitation of EF responses to enhance immunity through therapeutic and prophylactic interventions.

项目概要 滤泡外 (EF) B 细胞反应在气道腔内产生病毒特异性 IgM、IgG 和 IgA 以及流感病毒感染后 72 小时内的局部淋巴结，与病毒在时间上相关 清除。 EF 反应在动力学、功能和信号传导要求方面与较慢的反应不同 生发中心反应。 EF B 细胞反应在很大程度上被忽视，因为它在病原体中具有重要意义。 诱导免疫，因为它们被认为只产生短寿命的浆细胞和低亲和力抗体。 然而，与最近关于 BCR 和 BCR 之间高亲和力相互作用的要求的研究一致 抗原诱导 EF 反应，我们的研究表明，对流感 HA 的原型 EF 反应 A/Puerto Rico /8/34 在流感感染后长期产生高亲和力的保护性抗体。因此， 确定这种反应是原发性流感感染诱导的抗病毒免疫的重要组成部分。 然而，用佐剂中的灭活病毒进行免疫未能诱导 EF 反应，但确实诱导了 强大的生发中心，从而确定疫苗诱导的体液免疫的特定缺陷， 可能会降低其功效。因为诱导 EF 反应的信号是未知的，并且它们的保护性 能力尚不清楚，不能将它们用于治疗或预防用途。为了克服这个 知识差距 我们建议检验我们的假设，即先天 B 细胞直接信号传导驱动高亲和力 通过诱导强烈的 EF 反应，产生长期保护性抗病毒体液免疫。具体目标#1 将 使用基因靶向小鼠来识别负责 EF 发展的受体和信号通路 流感感染后并补体灭活流感疫苗及其相应配体 生成 EF 响应。目标 2 将描述这些信号通路的分子靶标 遵循流感 HA 特异性 B 细胞的命运，B 细胞分化为 EF 浆母细胞。目标3将 评估 EF 和 GC B 细胞反应的质量和保护能力。这些成果的成功 研究将通过证明 EF 对感染的反应可以产生概念上的进步 高亲和力抗体反应并提供免疫保护。配体鉴定、信号传导 驱动 EF 反应的途径和基因靶点将增加关于 EF 反应的基础知识 B 细胞分化机制，并为利用 EF 反应增强 通过治疗和预防干预来增强免疫力。