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.