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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (O1))
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Colombini-Hatch, Sandra
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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West, T Eoin; Myers, Nicolle D; Chantratita, Narisara et al. (2014) NLRC4 and TLR5 each contribute to host defense in respiratory melioidosis. PLoS Negl Trop Dis 8:e3178
Chantratita, N; Tandhavanant, S; Myers, N D et al. (2014) Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis. Genes Immun 15:63-71
Myers, Nicolle D; Chantratita, Narisara; Berrington, William R et al. (2014) The role of NOD2 in murine and human melioidosis. J Immunol 192:300-7
Schwarz, Sandra; Singh, Pragya; Robertson, Johanna D et al. (2014) VgrG-5 is a Burkholderia type VI secretion system-exported protein required for multinucleated giant cell formation and virulence. Infect Immun 82:1445-52
Chantratita, Narisara; Tandhavanant, Sarunporn; Myers, Nicolle D et al. (2014) Common TLR1 genetic variation is not associated with death from melioidosis, a common cause of sepsis in rural Thailand. PLoS One 9:e83285
Chantratita, Narisara; Tandhavanant, Sarunporn; Myers, Nicolle D et al. (2013) Survey of innate immune responses to Burkholderia pseudomallei in human blood identifies a central role for lipopolysaccharide. PLoS One 8:e81617
West, T Eoin; Chantratita, Narisara; Chierakul, Wirongrong et al. (2013) Impaired TLR5 functionality is associated with survival in melioidosis. J Immunol 190:3373-9
West, T E; Chierakul, W; Chantratita, N et al. (2012) Toll-like receptor 4 region genetic variants are associated with susceptibility to melioidosis. Genes Immun 13:38-46
West, T Eoin; Myers, Nicolle D; Liggitt, H Denny et al. (2012) Murine pulmonary infection and inflammation induced by inhalation of Burkholderia pseudomallei. Int J Exp Pathol 93:421-8
Schwarz, Sandra; West, T Eoin; Boyer, Frederic et al. (2010) Burkholderia type VI secretion systems have distinct roles in eukaryotic and bacterial cell interactions. PLoS Pathog 6:e1001068

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