PROJECT SUMMARY Lower respiratory tract infections, including pneumonia, are the most common cause of infection-related death worldwide. γδ T cells are highly conserved leukocytes possessing innate-like immune response characteristics. Enriched in the mucosa, γδ T cells may play an outsized role in regulating pulmonary inflammatory responses and have been proposed as a basis for novel immunotherapies. However, data concerning the inflammatory role of pulmonary γδ T cells during pneumonia in humans are limited. Dr. Shelton Wright is a pediatric intensive care physician-scientist whose goal is to obtain the necessary training to become an independent translational investigator of pulmonary host defense. He has established a translational research program that has identified a critical role of γδ T cells in pulmonary melioidosis, a highly lethal cause of pneumonia. Based on these findings, he has developed a central hypothesis that host resistance to pulmonary melioidosis is dependent on an IL-17+ γδ T cell inflammatory response. Dr. Wright's research goal is to determine the mechanisms underlying the host γδ T cell inflammatory response during severe lung infection. Using pulmonary melioidosis as a model for severe lung infection, Dr. Wright will test his hypothesis through the following 3 Aims: 1) Determine the role of γδ T cells in lung inflammation during pulmonary melioidosis in vivo; 2) Identify differential human γδ T cell inflammatory responses to B. pseudomallei infection in the ex-vivo lung compared to peripheral blood; and 3) Characterize γδ T cell activation in patients with early pulmonary melioidosis. The Career Development Plan for this grant proposal will provide Dr. Wright with critical training in pulmonary immunology, transcriptomics and high containment pathogen research. Dr. Wright has leveraged the outstanding training infrastructure at the University of Washington and its affiliates to bring together a wide array of experts in these fields to provide targeted mentorship for this proposal. Dr. Wright's multidisciplinary team of mentors will greatly complement his proposed research project along with a carefully selected didactic program. The data generated by his proposal and the skillsets developed from his training program will significantly facilitate Dr. Wright's goal of developing into an independent translational physician-scientist investigating the mechanisms of pulmonary host defense during severe lung infection.