The generation and protective function of lung tissue resident memory T cells following SARS-CoV-2 infection or vaccination

项目摘要/摘要 冠状病毒病2019年(新冠肺炎)，由严重急性呼吸综合征冠状病毒2号(SARS- CoV-2)已爆发为一场全球大流行，造成重大生命损失，显著的经济影响和 重大的长期医疗影响，目前仍在研究中。尽管提供了令人印象深刻的保护 通过目前主要由抗体中和病毒介导的SARS-CoV-2疫苗，这些 抗体随着时间的推移而减弱，新的病毒变种出现了，对这些抗体不太敏感。 一个主要的问题是，记忆T细胞在感染SARS-CoV-2期间是否提供了更持久的保护。 先前的研究表明，从2003年开始从SARS-CoV感染中康复的人表现出SARS-CoV- 外周血中的特异性记忆CD8 T细胞反应长达11年，病毒特异性抗体 6年后可检测到，与MERS冠状病毒多肽1，2没有交叉反应。对于当前的大流行， 然而，我们开始了解在血液中感染SARS-Cov2后形成什么类型的记忆T和B细胞 我们不知道这些反应的寿命有多长。更重要的是，我们对肺部疾病知之甚少。 SARS-CoV-2感染后在肺内形成的记忆T和B细胞，以及基于已有的 从其他病毒中学到的，这些可能是最具保护性的记忆细胞，需要优越的长期- 对再次感染的长期免疫力。 在Teijaro、Kaech和Farber实验室之间的这项合作提案中，我们将世界- 抗病毒免疫和肺部发病机制、免疫记忆和人类免疫学方面的专业知识 目的：研究SARS-CoV-2肺内滞留TRM细胞的发育及保护作用。在目标1中，我们将 研究SARS-CoV-2TRM在hACE2转基因小鼠肺内发育的基础 通过TGFBR2和TGFBR2的遗传扰动，确定长期免疫是否需要TRM T细胞中的Smad4，这是TRM分化所必需的，以及循环的耗竭。 存储单元。在目标2中，我们将研究肺trm细胞是否参与了mrna所提供的保护。 疫苗以更好地了解记忆T细胞在介导对SARS-CoV-2和 值得关注的变种(VOC)。最后，在目标3中，我们将我们在小鼠中的研究扩展和补充到Dr。 Farber的人类供体资料库评估SARS-CoV-2感染后人类记忆的形成和 接种疫苗。我们希望回答SARS后形成哪些类型的记忆T细胞的基本问题-- CoV-2感染，并提供对该病毒和VOCs的长期保护性免疫。这些研究将 提供与SARS-CoV后形成的免疫记忆质量有关的关键信息- 2在小鼠和人类中感染，并将用于指导当前和未来的疫苗开发。

Project Summary/Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), has exploded into a global pandemic causing significant loss of life, pronounced economic impact and significant long-term medical impacts which are still being characterized. Despite impressive protection afforded by the current SARS-CoV-2 vaccines which are primarily mediated by antibody neutralization of virus, these antibodies wane over time and new viral variants have emerged that are less susceptible toby these antibodies. A major question is whether memory T cells afford more long-lasting protection during SARS-CoV-2 infection. Prior studies showed that people who recovered from SARS-CoV infection from 2003 exhibited SARS-CoV- specific memory CD8+ T cell responses in peripheral blood for up to 11 years, virus-specific antibodies were not detectable at 6 years, and there was no cross-reactivity with MERS-CoV peptide1,2. For the current pandemic, we are starting to learn what types of memory T and B cells form after SARS-Cov2 infection in the blood, however we have no idea the longevity of these responses. More importantly, we know very little about the pulmonary memory T and B cells that form in the lung after SARS-CoV-2 infection and, based on what has been learned from other viruses, these may be the most protective memory cells needed for superior long- term immunity to reinfection. In this collaborative proposal between the Teijaro, Kaech and Farber labs, we bring together world- class expertise in anti-viral immunity and lung pathogenesis, immunological memory and human immunology to study the development and protective role of lung-resident TRM cells in SARS-CoV-2. In Aim 1, we will study the fundamentals of SARS-CoV-2 TRM development in the lungs of hACE2-transgenic mice and determine whether TRM are required for long- term immunity, through genetic perturbations of Tgfbr2 and Smad4 in T cells, which are differentially required for TRM differentiation3, and the depletion of circulating memory cells. In Aim 2, we will examine if lung TRM cells contribute to the protection afforded by mRNA vaccines to better understand the role, if any, of memory T cells in mediating protection to SARS-CoV-2 and notable variants of concern (VOC). Lastly, in Aim 3, we extend and complement our studies in mice to Dr. Farber’s human donor repository to assess human memory formation following SARS-CoV-2 infection and vaccination. We hope to answer the basic question of which types of memory T cells form after SARS- CoV-2 infection and confer long-term protective immunity to this virus and VOCs. These studies will provide critical information related to the quality of immunological memory that forms after SARS-CoV- 2 infection in mice and humans and will serve to guide current and future vaccine development.