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

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.