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

项目总结 流感病毒是人类呼吸道病原体，在1000-4900万人和650,000人中引起轻微到严重的疾病 每年的死亡人数。这项建议的目标是确定提供保护的细胞免疫反应。 以确定首次接触流感后在我们体内留下的免疫学后果。 对流感的保护是由保护的免疫相关因素决定的--与 减少了对感染的易感性。自然流感感染或接种疫苗后产生的抗体- 然而，即使在抗体效价升高的患者中，最近的疫苗效力也有所减弱，这表明 抗体本身并不能提供完全的保护。细胞免疫(CMI)的组成部分，包括先天免疫 免疫细胞和抗原特异性T细胞也可能是预防流感的关键。然而，不同的CMI 人类对流感的保护作用没有得到充分的定义，这使得人们在理解抗流感反应方面存在差距 以及限制下一代疫苗设计的范围。目标1使用生物学(流式细胞术)和计算 (统计建模)对从两个已建立的人类队列收集的样本进行分析，以确定不同的CMI 保护个人免受流感影响的反应，与CMI相关的假设提供了独立的保护 来自抗体反应。有趣的是，童年是培养对流感免疫力的关键时期，因为第一次接触 这种病毒通常在婴儿期，可以影响终生反应的强度和特异性。最初的抗原暴露发生在 自然感染或接种疫苗的背景；然而，首次接触背景的免疫学后果是 未知。此外，评估印记在人类中是具有挑战性的，因为还没有对流感幼稚队列进行研究。目标 2假设第一次接触流感的背景对流感特异性T细胞的发育和功能具有持久的影响。 利用在一项招募免疫天真婴儿的新研究中收集的样本，Aim 2将确定 (接种；感染)最初的流感抗原暴露通过生物影响抗流感免疫的发展 (T细胞功能和特异性)和计算(T细胞谱系多样性)方法。 对大型人类队列的独特访问使这项成功识别保护性CMI相关性的建议处于有利地位 在真实世界的环境中，并将在调查幼稚出生队列中最初的流感抗原暴露方面具有开创性。 导师保罗·G·托马斯博士的支持和指导，他是一位多产的研究员，有十年的高影响力记录 免疫学研究，圣犹大儿童研究医院，一家拥有超过35个核心的世界级研究机构 设施和专门的博士后发展计划，使拟议的研究取得成功，并支持培训 在四个确定的领域，包括免疫学专业知识、科学生产力、专业发展和科学 沟通。总之，这项建议将继续NIAID了解、治疗和预防传染病的使命 通过向下一代疫苗设计和儿童最佳实践疫苗实施提供信息，同时 促进博士后申请者自主研究发展。

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.