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

项目摘要--总体 La Jolla HIPC团队将专注于导致上下部传染病的病原体 导致大量死亡和发病的呼吸道疾病。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的CD4和CD8T细胞在应对 SARS-CoV-2、普通感冒冠状病毒等重要呼吸道病原体的自然感染 (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的疫苗接种后产生的抗原特异性T细胞的免疫球蛋白 不同平台上的病原体，如减毒病原体(卡介苗、黄热病(YF))、纯化蛋白(无细胞 百日咳杆菌(PT)疫苗)、病毒载体(强生、SARS-CoV-2)和信使核糖核酸(莫德纳和辉瑞)。 在项目1中，我们将进行纵向分析，以确定抗原特异性的持久性和可塑性 自然感染SARS-CoV-2和接种疫苗后的T细胞反应。我们将研究T细胞的特异性反应 在以前未接种过疫苗的捐赠者中接种不同疫苗平台后感染SARS-CoV-2，以及在 以前自然感染SARS-CoV-2的接种疫苗个人的纵向队列。在平行研究中， 我们将分析自然感染的未接种疫苗的献血者对SARS-CoV-2的T细胞反应。我们还将分析 接受YF和PT疫苗接种的两个先前登记的队列中的T细胞反应；在这两个队列中 本课程将研究T细胞对CCC病毒的自然进化和持久性。 在项目2中，我们将对结核分枝杆菌特异性T细胞的免疫球蛋白进行纵向分析。在这里，我们将在 我们在上一次重债穷国供资期间在确定与潜在和 活动性结核病以及卡介苗接种。具体地说，我们将描述两者的纵向IMS 治疗期间的活动性和潜伏性结核病。同时，我们将描述成人的纵向IMS (再次)接种卡介苗，并鉴定肺内结核分枝杆菌特异性T细胞的免疫反应。 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 针对感染肺部的常见病原体的抗原特异性肺TRM，例如：病毒(流感、RSV、 副流感、偏肺病毒、SARS-CoV-2、CCC)、细菌(肺炎球菌、肺炎支原体、结核分枝杆菌)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。 在自然感染和接种疫苗之后。项目之间的协同作用将允许产生交叉- 呼吸道病原体/疫苗的可比大规模单细胞T细胞特征。

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.