Investigating the cellular responses to influenza virus infection and the origins of first exposure immune imprinting

研究细胞对流感病毒感染的反应以及首次暴露免疫印记的起源

• 批准号: 10315620
• 负责人: Robert C Mettelman
• 金额: $ 6.64万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315620
• 关键词: Investigating; cellular; responses; influenza; virus

PROJECT SUMMARY Influenza viruses are human respiratory pathogens causing mild to severe illness in 10-49 million individuals and 650,000 deaths annually. The objectives of this proposal are to determine the cellular immune responses that provide protection from influenza disease and to determine the immunologic consequences imprinted within us following first exposure to influenza. Protection against influenza is determined by immune correlates of protection– the immune factors that associate with reduced susceptibility to infection. Antibodies generated following natural influenza infection or vaccination are well- studied correlates; however, recent vaccine efficacy has waned even in patients with elevated antibody titers suggesting that antibodies alone do not provide complete protection. Components of cell-mediated immunity (CMI) including innate immune cells and antigen-specific T cells may also be critical in protecting against influenza. However, distinct CMI correlates of protection to influenza are not fully defined in humans leaving a gap in understanding anti-influenza response and limiting the scope of next generation vaccine design. Aim 1 employs biologic (flow cytometry) and computational (statistical modeling) analyses of samples collected from two established human cohorts to determine the distinct CMI responses that protect individuals from influenza, with the hypothesis that CMI correlates provide protection independent from antibody responses. Interestingly, childhood is a crucial time in developing immunity to influenza as first contact with the virus, often during infancy, can imprint intensity and specificity of lifelong responses. Initial antigen exposure occurs in the context of either natural infection or vaccination; however, the immunologic consequences of first exposure context are unknown. Further, evaluating imprinting is challenging in humans as no influenza-naïve cohort has yet been studied. Aim 2 posits that the context of first influenza exposure has lasting effects on influenza-specific T cell development and function. Utilizing samples collected in a novel study enrolling immunologically naïve infants, Aim 2 will determine how the context (vaccination; infection) of initial influenza antigen exposure impacts anti-influenza immune development through biologic (T cell function and specificity) and computational (T cell repertoire diversity) methods. The unique access to large human cohorts positions this proposal to successfully identify protective CMI correlates in a real-world setting and will be groundbreaking in investigating initial influenza antigen exposure in a naïve birth cohort. The support and guidance of mentor Dr. Paul G. Thomas, a prolific investigator with a decade-long record of high-impact research in immunology, and St. Jude Children’s Research Hospital, a world-class research institution with over 35 core facilities and dedicated postdoctoral development programs, enable the success of the proposed research and bolster training in four defined areas including immunology expertise, scientific productivity, professional development, and scientific communication. Together, this proposal will continue the mission of NIAID to understand, treat and prevent infectious disease by informing next generation vaccine design and best-practice vaccine implementation in children, all while promoting the independent research development of the postdoctoral applicant.

项目摘要 流感病毒是人类呼吸道病原体，在1000万至4900万人和65万人中引起轻度至重度疾病。 每年死亡。该提案的目的是确定提供保护的细胞免疫应答， 流感疾病，并确定免疫后果印在我们第一次接触流感。 对流感的保护是由保护的免疫相关因素决定的， 降低了感染的敏感性。自然感染流感或接种疫苗后产生的抗体是很好的- 研究相关性;然而，最近的疫苗效力已经减弱，即使在抗体滴度升高的患者中也表明， 单独的抗体不能提供完全的保护。细胞介导免疫（CMI）的组成部分，包括先天性 免疫细胞和抗原特异性T细胞在预防流感方面也可能是至关重要的。然而，不同的CMI 人类对流感的保护相关性尚未完全确定，这使得对抗流感反应的理解存在空白 并限制了下一代疫苗设计的范围。目的1采用生物（流式细胞术）和计算 （统计建模）分析从两个已建立的人类队列收集的样本，以确定不同的CMI 保护个人免受流感的反应，假设CMI相关提供独立的保护 抗体反应。有趣的是，童年是对流感产生免疫力的关键时期，因为第一次接触 这种病毒通常在婴儿期出现，可在终生免疫反应中留下强度和特异性的印记。初始抗原暴露发生在 自然感染或接种疫苗的情况下;然而，第一次暴露的免疫学后果是 未知此外，在人类中评估印迹具有挑战性，因为尚未研究过流感初治队列。目的 2假定首次流感暴露的背景对流感特异性T细胞发育和功能具有持久影响。 利用在一项招募免疫学幼稚婴儿的新研究中收集的样本，Aim 2将确定环境如何影响免疫学幼稚婴儿的免疫学行为。 初始流感抗原暴露（疫苗接种;感染）通过生物学效应影响抗流感免疫发育 （T细胞功能和特异性）和计算（T细胞库多样性）方法。 对大型人类队列的独特访问使这一提议成功地确定了保护性CMI相关物 在现实世界的环境中，这将是开创性的，在调查初始流感抗原暴露在一个天真的出生队列。 在导师Paul G.托马斯是一位多产的调查员，有着长达十年的高影响力记录。 Jude Children's Research Hospital是一家世界级的研究机构，拥有超过35个核心研究中心。 设施和专门的博士后发展计划，使拟议的研究和加强培训的成功 在四个定义的领域，包括免疫学专业知识，科学生产力，专业发展， 通信总之，这一建议将继续NIAID的使命，以了解，治疗和预防传染性疾病， 与此同时，通过为下一代疫苗设计和儿童疫苗最佳实践实施提供信息来预防疾病 促进博士后申请人的独立研究发展。