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: 10680531
• 负责人: Robert C Mettelman
• 金额: $ 7.38万
• 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/10680531
• 关键词: Accounting; Adult; Affect; Age; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Area; Bioinformatics; Biological; Birth; Blood specimen; Body mass index; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cellular Immunity; Cellular Structures; Cessation of life; Child; Childhood; Collaborations; Communicable Diseases; Communication; Core Facility; Correlation Studies; Dedications; Development; Disease; Disease Outcome; Educational process of instructing; Enrollment; Epitopes; Ethnic Origin; Etiology; Exposure to; Flow Cytometry; Frequencies; Genomics; Goals; Grant; Heterogeneity; Human; Image; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunologic Factors; Immunologics; Immunology; Individual; Infant; Infection; Influenza; Influenza vaccination; Institution; Logistic Regressions; Longitudinal Studies; Measurable; Membrane Proteins; Memory; Mentors; Methods; Mission; Modeling; National Institute of Allergy and Infectious Disease; Patients; Persons; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Production; Productivity; Program Development; Reporting; Research; Research Personnel; Respiratory Tract Infections; Saint Jude Children' s Research Hospital; Sampling; Seasons; Serology; Specificity; Statistical Models; T cell response; T-Cell Development; T-Lymphocyte; T-cell receptor repertoire; Time; Training; Vaccination; Vaccine Design; Vaccines; Viral; Virus; Writing; anti-influenza; antigen-specific T cells; antiviral immunity; cohort; cytokine; design; imprint; infancy; infection risk; influenza infection; influenza virus vaccine; influenzavirus; novel; novel vaccines; older patient; pediatric patients; prevent; programs; research and development; respiratory; respiratory pathogen; response; seasonal influenza; sex; success; supportive environment; vaccine efficacy

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100-49万个人和65万人中导致轻度至严重疾病 每年死亡。该提案的目标是确定可保护免受保护的细胞免疫反应 流感疾病并确定首次受到影响后，我们内心造成的免疫学后果。 保护影响是由保护的免疫力确定的 - 关联的免疫反应器 感染的敏感性降低。自然有影响力感染或疫苗接种后产生的抗体是很好的 研究的相关性；但是，即使在抗体滴度升高的患者中，最近的疫苗效率也会降低，这表明 仅抗体就不能提供完全保护。细胞介导的免疫（CMI）的成分，包括先天 免疫细胞和抗原特异性T细胞也可能对保护影响至关重要。但是，CMI独特 人类没有完全定义与影响力的保护的相关性 并限制下一代疫苗设计的范围。 AIM 1员工生物学（流式细胞仪）和计算 （统计建模）对从两个已建立的人类同类群体收集的样品的分析，以确定不同的CMI 保护个体免受影响力的反应，并假设CMI关联提供独立的保护 来自抗体反应。有趣的是，童年是发展豁免权的关键时期，作为首次接触的影响 该病毒通常在婴儿期，可以构成终身反应的强度和特异性。初始抗原暴露发生在 自然感染或疫苗的背景；但是，首次接触环境的免疫学后果是 未知。此外，在人类中，评估印迹是具有挑战性的，因为尚未研究任何影响力。目的 2认为，第一影响的上下文对影响特定的T细胞的开发和功能具有持久的影响。 利用在一项新的研究中收集的样品，从免疫学上注册，AIM 2将决定背景如何 （疫苗接种；感染）初始影响者抗原暴露会通过生物学影响抗激素的免疫发育 （T细胞功能和特异性）以及计算（T细胞库多样性）方法。 对大型人类人群的独特访问将此提出成功识别的CMI相关的提案定位 在现实环境中，将在调查幼稚的出生队列中最初的影响力抗原暴露时开创性。 导师保罗·托马斯（Paul G. Thomas）博士的支持和指导，他是一位多产的调查员，有十年的高影响力记录 免疫学研究和圣裘德儿童研究医院，这是一家拥有35多个核心的世界一流研究机构 设施和专门的博士后开发计划，使拟议的研究和支持培训的成功取得了成功 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。这项提议将继续努力的使命，以理解，治疗和预防感染力 通过告知下一代疫苗设计和儿童最佳实践疫苗的疾病， 促进博士后申请人的独立研究开发。