Project Summary/Abstract Respiratory infections account for millions of hospitalizations and deaths each year globally. Notably, seasonal Influenza virus infections accounts for a significant fraction of these statistics, and attempts to vaccinate against these strains have mixed efficacy. Current strategies to immunize against influenza involve eliciting antibody responses against surface glycoproteins, but the high mutation rate of influenza allows for immune evasion against antibodies. Therefore, the design and development of influenza vaccines that provide long-lived cellular immunological memory and offers broad protection represents a major unmet clinical need. To this end, a vaccine that elicits memory CD8+ T cells, which recognize viral epitopes that are conserved across diverse flu strains, may be necessary for optimal protection. However, the cell-intrinsic molecular events involved in the formation of memory CD8+ T cells in the lung are poorly characterized. Additionally, it has been shown that lung tissue immunity wanes over time, resulting in a narrow window of protection against secondary infection. This proposal seeks to investigate how modulation of chromatin states influences the differentiation of lung resident memory (TRM) cells that are protective against influenza infection, with the hypothesis that the lineage-defining transcription factors T-bet and EOMES tunes the activity of the SWI/SNF chromatin remodeling complex to imprint chromatin states that promote TRM versus circulating memory (TCIRCM) cell fates. Three specific aims are proposed to interrogate this hypothesis. The first aim will define the T-bet and EOMES-bound regulatory elements that are permissive and/or instructive for lung TRM and TCIRCM cell differentiation. The second aim seeks to define chromatin states in TCIRCM and TRM cells that are dependent on BRG1, a core ATPase subunit of the SWI/SNF chromatin remodeling complex. Finally, the third aim will evaluate the importance of BRG1 in establishing chromatin states that promoting or suppressing lung TRM formation in vivo. In summary, this proposal seeks to provide insight into the molecular machinery that control the formation of lung TRM formation after flu infection. Understanding the mechanisms governing this process will enhance our capacity to induce long-lived protective cellular immunity in a vaccine setting against respiratory infections. This application details the applicant’s training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of academic research as an independent scientist.

Project Narrative Respiratory infections like influenza are a significant contributor to global morbidity and mortality, especially in vulnerable populations like the elderly. Understanding the mechanisms by which immunological memory is formed and maintained against these pathogens is critical for the rational design of effective vaccines. This proposal seeks to explore the dynamics of chromatin remodeling that orchestrate the generation of memory T cells that reside in the lung to offer frontline protection against respiratory infection.