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

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.