Rare Airway Cell Function in Post-Viral Chronic Inflammation - PROJECT SUMMARY The airway epithelium serves as a barrier between the aerosol environment and the underlying submucosa. Inhaled air often carries noxious agents and pathogens that can injure the lung. Severe lung injury can lead to persistent inflammation, dysplastic repair, and permanent loss of gas exchange surface area. Injury from common respiratory viral infection, such as influenza and SARS-CoV-2, can lead to chronic lung disease or exacerbation of lung conditions. Airway cells contribute to regeneration following lung injury, although the heterogeneity of airway cell identity following lung repair is incompletely understood. My research centers on rare airway cell types and their function in the post-viral lung. We have previously studied the differentiation of an unexpected airway cell type, tuft cells, during repair. Using single nucleus expression and accessible chromatin sequencing to survey airway cells following influenza injury, we identify a rare airway cell present in the post-viral lung, Microfold (M) cells. M cells have not been studied in the lung but in other contexts associate with lymphoid follicles, where they function to capture and deliver luminal antigens and secrete chemokines. The proposed research will identify pulmonary M cell progenitors and determine mechanisms required for M cell differentiation. This proposal uncovers M cells as part of a follicle associated epithelium (FAE) overlying induced bronchus associated lymphoid tissue (iBALT), implying M cells function to promote mucosal immune responses. The proposed aims will define the role of M cells in lung immune surveillance. My future research program will test the role of M cells in secondary bacterial infection, as much of the morbidity of pulmonary influenza infections can be attributed to secondary bacterial infection. Examining interactions between M cells and the immune compartment will contribute to our understanding of immune regulation during post-viral chronic inflammation. A second outcome from my focus on airway repair following severe influenza infection is an effort to promote the resolution of basal-like scar tissue into normal alveolar epithelium. Bronchiolization of the distal airway is a hallmark of multiple human lung diseases, and providing regenerative therapies will require detailed understanding of the regulation of basal-like cells. I propose defining a genetic mouse model that promotes differentiation of alveolar basal-like cells into alveolar epithelial cell fates. My primary mentor is Dr. Xin Sun, a leader in the field of lung biology who has made fundamental discoveries in lung development and disease. I will receive guidance from my mentorship committee, a group with expertise in lung biology and physiology, immunology and epigenetics. The proposed experiments and training plan will further my skills in bioinformatics and immunology. This research will be conducted at University of California San Diego, a leading research institution with necessary resources and a collaborative scientific community.
