Respiratory pathogen-specific T cell signatures following vaccination, natural infection, and treatment

疫苗接种、自然感染和治疗后呼吸道病原体特异性 T 细胞特征

• 批准号: 10419449
• 负责人: Alessandro Sette
• 金额: $ 239.15万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419449
• 关键词: 2019-nCoV; ATAC-seq; Address; Adult; Antigens; Atlases; Attenuated; Bacille Calmette-Guerin vaccination; Bacteria; Blood; Bordetella pertussis; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Assay; Clinical; Common Cold; Communicable Diseases; Communication; Coronavirus; Disease; Enrollment; Ensure; Epitopes; Evolution; Flow Cytometry; Funding; Generations; Goals; Immune; Immune response; Infection; Influenza; Lead; Longitudinal Studies; Longitudinal cohort; Lower respiratory tract structure; Lung; Memory; Messenger RNA; Molecular; Morbidity - disease rate; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Pertussis; Pertussis Vaccine; Phenotype; Play; Pneumovirus; Property; Proteins; Recurrence; Research Design; Resources; Respiratory Tract Infections; Respiratory syncytial virus; Risk; Role; SARS-CoV-2 infection; Services; Severity of illness; Sorting - Cell Movement; Streptococcus pneumoniae; Structure of parenchyma of lung; Systems Biology; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Technology; Time; Tissues; Vaccinated; Vaccination; Vaccinee; Vaccines; Viral; Viral Vector; Virus; Yellow Fever; adaptive immunity; antigen-specific T cells; base; biomarker panel; burden of illness; cohort; cost effective; data management; design; epigenome; innovation; longitudinal analysis; mortality; pandemic influenza; pathogen; pathogenic fungus; programs; respiratory pathogen; response; success; synergism; transcriptome; transcriptomics; unvaccinated; vaccine platform

Project Summary – Overall The La Jolla HIPC team will focus on pathogens causing infectious diseases of the upper and lower respiratory tract that lead to substantial mortality and morbidity. Our approach is unique and innovative, as it focuses on defining immune signatures (IMS) of antigen-specific CD4 and CD8 T cells generated in response to natural infection with important respiratory pathogens such as SARS-CoV-2, Common Cold Coronaviruses (CCC), influenza, Respiratory Syncytial Virus (RSV) and Mycobacterium tuberculosis (Mtb). Likewise, our Program will investigate IMS of antigen-specific T cells generated following vaccination against a diverse array of pathogens in different platforms like attenuated pathogens (BCG, yellow fever (YF)), purified proteins (acellular Bordetella pertussis (PT) vaccines), viral vectors (J&J, SARS-CoV-2) and mRNA (Moderna and Pfizer). In Project 1, we will perform longitudinal analysis to determine persistence and plasticity of antigen-specific T cell responses following natural SARS-CoV-2 infection and vaccination. We will study T cell responses specific to SARS-CoV-2 following vaccination with different vaccine platforms in previously-unvaccinated donors, and in a longitudinal cohort of vaccinated individuals previously naturally-infected with SARS-CoV-2. In parallel studies, we will analyze T cell responses to SARS-CoV-2 in naturally-infected unvaccinated donors. We will also analyze T cell responses in two previously-enrolled cohorts who received YF and PT vaccinations; in both cohorts the natural evolution and persistence of T cell responses to CCC viruses will be investigated. In Project 2, we will perform longitudinal analysis of the IMS of Mtb-specific T cells. Here, we will build on our progress made during the previous HIPC funding period to characterize the IMS associated with latent and active TB disease as well as BCG vaccination. Specifically, we will characterize the longitudinal IMS of both active and latent TB during treatment. In parallel, we will characterize the longitudinal IMS of adults (re)vaccinated with BCG, and characterize the IMS of Mtb-specific T cells in the lung. In Project 3, we will determine the molecular properties of pathogen-specific lung tissue-resident memory T cells (TRM). Our goal is to establish a single-cell atlas of the transcriptome, epigenome, and T cell receptor (TCR) of antigen-specific lung TRM targeting common pathogens that infects the lungs such as: viral (influenza, RSV, para influenza, meta pneumovirus, SARS-CoV-2, CCC), bacterial (pneumococcus, PT, Mtb) and fungal pathogens. The longitudinal study design will enable assessment of plasticity and persistence of lung TRM cells following natural infection and vaccination. The synergy between Projects will allow the generation of cross- comparable large-scale single-cell T cell signatures for respiratory pathogens/vaccines.

项目概要-总体 拉霍亚重债穷国小组将重点研究引起上下游国家传染病的病原体。 导致大量死亡和发病。我们的方法是独特和创新的，因为它 重点是定义抗原特异性CD 4和CD 8 T细胞的免疫特征（IMS）， 自然感染重要的呼吸道病原体，如SARS-CoV-2、普通感冒冠状病毒 (CCC)流感、呼吸道合胞病毒（RSV）和结核分枝杆菌（Mtb）。同样，我们的 该计划将研究针对不同阵列接种疫苗后产生的抗原特异性T细胞的IMS 病原体在不同的平台，如减毒病原体（卡介苗，黄热病（YF）），纯化的蛋白质（无细胞 百日咳杆菌（PT）疫苗）、病毒载体（J&J，SARS-CoV-2）和mRNA（Moderna和Pfizer）。 在项目1中，我们将进行纵向分析，以确定抗原特异性抗体的持久性和可塑性。 自然SARS-CoV-2感染和疫苗接种后的T细胞应答。我们将研究T细胞的反应， 在先前未接种疫苗的供体中接种不同疫苗平台后， 一个纵向队列的接种疫苗的个人以前自然感染SARS-CoV-2。在平行研究中， 我们将在自然感染的未接种疫苗的供体中分析T细胞对SARS-CoV-2的应答。我们还将分析 接受YF和PT疫苗接种的两个先前招募的队列中的T细胞应答;在两个队列中， 将研究T细胞对CCC病毒应答的自然进化和持久性。 在项目2中，我们将对Mtb特异性T细胞的IMS进行纵向分析。在这里，我们将建立在 我们在前一个重债穷国资助期内取得的进展， 活动性结核病以及卡介苗接种。具体来说，我们将描述纵向IMS的两个 活动性和潜伏性结核病。同时，我们将描述成人的纵向IMS （再）接种BCG，并表征肺中Mtb特异性T细胞的IMS。 在项目3中，我们将确定病原体特异性肺组织驻留记忆T的分子特性， 细胞（TRM）。我们的目标是建立转录组、表观基因组和T细胞受体（TCR）的单细胞图谱 抗原特异性肺TRM靶向感染肺的常见病原体，例如：病毒（流感，RSV， 帕拉流感病毒、Meta肺炎病毒、SARS-CoV-2、CCC）、细菌（肺炎球菌、PT、Mtb）和真菌 病原体纵向研究设计将能够评估肺TRM细胞的可塑性和持久性 自然感染和接种疫苗后。项目之间的协同作用将允许产生交叉- 用于呼吸道病原体/疫苗的可比较的大规模单细胞T细胞特征。