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

基本信息

批准号：
10548117
负责人：
Robert C Mettelman
金额：
$ 6.98万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
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/10548117
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 Development Disease Disease Outcome Educational process of instructing Enrollment 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 Lead 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&apos s Research Hospital Sampling Seasons Serology Specificity Statistical Models T cell response T-Cell Development T-Lymphocyte T-Lymphocyte Epitopes 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

项目摘要

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.

项目概要流感病毒是人类呼吸道病原体，可导致 10-4900 万人和 65 万人罹患轻度至重度疾病该提案的目标是确定提供保护的细胞免疫反应。流感疾病并确定首次接触流感后对我们造成的免疫后果。对流感的保护是由保护的免疫相关性决定的——与相关的免疫因素自然流感感染或接种疫苗后产生的抗体对感染的敏感性降低。研究了相关性；然而，即使在抗体滴度升高的患者中，最近的疫苗功效也有所减弱，这表明单独的抗体不能提供细胞介导免疫 (CMI) 的完整保护，包括先天性免疫。免疫细胞和抗原特异性 T 细胞对于预防流感也可能至关重要，但 CMI 不同。人类对流感保护的相关性尚未完全确定，在理解抗流感反应方面留下了空白目标 1 采用生物（流式细胞术）和计算技术，限制下一代疫苗设计的范围。（统计模型）分析从两个已建立的人类队列中收集的样本，以确定不同的 CMI 保护个人免受流感影响的反应，假设 CMI 相关，提供独立的保护从抗体反应来看，童年是首次接触流感的关键时期。病毒通常在婴儿期会影响终生反应的强度和特异性。然而，自然感染或疫苗接种的情况下，首次暴露的免疫后果是此外，评估人类印记具有挑战性，因为尚未研究过流感初治人群。 2 假设首次接触流感的环境对流感特异性 T 细胞的发育和功能具有持久影响。利用一项招募免疫学上未接触过的婴儿的新研究中收集的样本，目标 2 将确定背景如何（疫苗接种；感染）初始流感抗原暴露通过生物制剂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。对大型人群的独特访问使该提案能够成功识别保护性 CMI 相关性在现实世界的环境中，这将在研究初始出生队列中的初始流感抗原暴露方面具有开创性。导师 Paul G. Thomas 博士的支持和指导，他是一位多产的研究者，拥有长达十年的高影响力记录免疫学研究，以及拥有超过 35 个核心的世界一流研究机构圣裘德儿童研究医院设施和专门的博士后发展计划，使拟议的研究取得成功并加强培训四个明确的领域，包括免疫学专业知识、科学生产力、专业发展和科学总之，该提案将继续履行 NIAID 了解、治疗和预防传染病的使命。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，同时促进博士后自主研究发展。