Pulmonary Pathogen-Recognition Pathways in Melioidosis

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DESCRIPTION (provided by applicant): Dr. West's career goal is to become a physican-scientist proficient in the translational study of mechanisms of pulmonary host defense, with a focus on bacterial respiratory infections, major causes of morbidity and mortality around the world. This career development application describes an integrated curriculum with two main objectives. The first objective is to provide the candidate with an in-depth knowledge of lung biology and immunology, and expanded training in laboratory methods to facilitate his career development toward independence. The second objective is to define pulmonary pathogen-recognition pathways in melioidosis, a lethal tropical infection caused by Burkholderia pseudomallei, a potential aerosol bioweapon. Dr. West's career development plan comprises didactic coursework, participation in scientific seminars and conferences, instruction in practical laboratory skills, close collaborations with a multidisciplinary group of scientists at University of Washington and abroad, intensive mentorship by an accomplished senior investigator, and oversight by an academic advisory committee. The research plan combines a wide assortment of gene knockout mice, in vitro studies of a variety of primary cells, sophisticated murine models of airborne disease, and access to specialized laboratory facilities. The specific aims of this proposal are: 1) to identify Toll-like receptors (TLRs) - transmembrane pathogen-recognition sensors - and downstream signaling pathways that mediate recognition of B. pseudomallei in vitro; 2) to define TLR signaling pathways in pneumonic melioidosis that influence specific components of innate and adaptive immunity; and 3) to determine the related role of the cytosolic ICE-protease-activating factor (IPAF)/caspase-1 signaling axis in melioidosis. In performing these studies, Dr. West will be closely supervised by Dr. Shawn Skerrett, a distinguished investigator whose research focus is the investigation of innate immunity in bacterial pneumonias using murine models of disease. Dr. West will also collaborate with an outstanding team of microbiologists, immunologists, and pathologists who share specific expertise in host-pathogen interactions, host and bacterial genetics, and mouse pneumonia models. The extensive academic and physical resources available to University of Washington scientists create an ideal environment for this career development training. Furthermore, the combined strengths of University of Washington's pulmonary, infectious diseases, and global health research programs will greatly facilitate Dr. West's progression toward his career goal. RELEVANCE (See instructions): This research directly addresses the stated mission of the NIH to pursue fundamental scientific knowledge that reduces the burden of illness and disability. These studies will increase our understanding of the lethal bacterial infection melioidosis, a growing public health problem, and may ultimately lead to the development of new treatments for this disease. The findings may also be applicable to other respiratory infections - leading causes of death and disability worldwide that disproportionately impact the poor.