Mechanistic Investigation of Gut Mycobiota in the Regulation of Lung Immunity and Disease (PA-20-188) Project summary/Abstract Asthma is a common, chronic airway inflammation that affects around 25 million Americans and 334 million people worldwide. In the mammalian gut, a diverse fungal community, known as the mycobiota shapes local and systemic host immune responses. Alterations of the gut fungal community are strongly associated with inflammatory disorders such as asthma, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases (IBD). Our recent findings suggest that intestinal specialized phagocytes could mediate the activation of fungal-primed T cells during allergic airway disease. Despite these, the precise mechanisms of gut- lung immune crosstalk are unknown. Based on these preliminary findings, we hypothesize that gut commensal fungi initiate antifungal immunity that affects lung immunity and modulates the progression of airway inflammation. The objectives of this project are to understand the molecular and cellular interplay between gut fungi and host lung immunity with specific focus on T cells. While the current proposal is to illuminate the basic effects of gut fungi on lung immunity and disease and to uncover mechanistic insights about gut-primed antifungal T cell activation and migration on the development of immune-mediated airway inflammation. My long-term goal is to investigate how the gut commensal mycobiota modulates the gut-systemic axis and impacts other pulmonary diseases, such as COPD and cystic fibrosis (CF). During my K99 training, I will be supervised by a team of mentors and scientific advisors with expertise in mycobiota, mucosal immunology, T cell biology and pulmonary diseases. They will provide strong support and mentorship in both research and career transition to independence, and help me to develop necessary technical skills and conceptual knowledge on lung immunity and antifungal T cells. This K99/R00 award will enable me to acquire the skills necessary for a deep analysis and understanding of the gut-systemic axis with the goal of creating novel therapies to treat asthma, COPD, CF, and other immune-related pulmonary diseases.