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.

项目摘要 滤泡外（EF）B细胞应答在气道腔中产生病毒特异性IgM、IgG和伊加 流感病毒感染后72 h局部淋巴结转移，与病毒感染时间相关 间隙EF反应在动力学、功能和信号要求方面与较慢的EF反应不同。 老年中心的反应。EF B细胞反应在很大程度上被认为在病原体中是重要的， 诱导免疫，因为它们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之间需要高亲和力相互作用的研究一致， 抗原诱导EF反应，我们的研究表明，一个原型EF反应HA流感 A/波多黎各/8/34在流感感染后长期产生高亲和力保护性抗体。因此，在本发明中， 鉴定这种应答是原发性流感感染诱导的抗病毒免疫的关键组成部分。 然而，用佐剂中的灭活病毒免疫不能诱导EF应答，但确实诱导了EF应答。 更强的生发中心，从而确定疫苗诱导的体液免疫中的特定缺陷， 可能会降低其功效。由于诱导EF反应的信号是未知的，并且它们的保护性 容量尚不清楚，它们不能用于治疗或预防用途。为了克服这个 知识差距，我们提出测试我们的假设，先天B细胞直接信号驱动高亲和力 通过诱导强烈的EF应答实现长期保护性抗病毒体液免疫。具体目标#1 使用基因靶向小鼠来识别负责EF发展的受体和信号通路 流感病毒感染后，用其相应的配体补充灭活流感疫苗 以产生EF响应。目标2将描绘这些信号通路的分子靶点， B细胞分化为EF血浆母细胞，遵循流感HA特异性B细胞的命运。目标3将 评估EF和GC B细胞应答的质量和保护能力。这些成功的结果 研究将通过证明EF对感染的反应可以产生 高亲和力抗体应答并提供免疫保护。配体的鉴定，信号传导 驱动EF反应的途径和基因靶点将增加有关EF反应的基础知识。 B细胞分化的机制，并打开了利用EF反应增强 通过治疗性和预防性干预措施提高免疫力。