The dynamic role of the alveolar macrophage during pulmonary bacterial infection

PROJECT SUMMARY Gram-negative bacterial pulmonary infections are responsible for significant morbidity and mortality worldwide. Burkholderia pseudomallei (Bps), a Gram-negative, facultatively intracellular bacterium and Tier 1 Select Agent, causes melioidosis, a leading etiology of pulmonary infections globally. Pulmonary infection with Bps causes severe and lethal pneumonia in mice, making aerosolized infection with Burkholderia spp. ideal models for studying the host response to Gram-negative bacterial pulmonary infections. Alveolar macrophages (AMs) are a distinct and critical component the initial host immune response to bacterial pathogens, yet little data exist on the role of AM in Gram-negative bacterial infection. Dr. Sarah Baker developed a research program to define the role of the AM in host response during Gram-negative bacterial pneumonia using a murine model of pulmonary melioidosis. She aims to determine the innate immune function of the AM during early pulmonary Gram-negative bacterial infection and define the role of the AM as a coordinator of the inflammatory response to Gram-negative bacterial infection during recovery from pneumonia. With the completion of these Aims, Dr. Baker will elucidate the significance of the AM as an intracellular replication niche for Burkholderia spp. during pulmonary infection and the mechanisms by which the AM orchestrates the pulmonary inflammatory milieu during recovery from bacteria-induced pulmonary injury. This improved understanding of host-pathogen interactions in the lung is crucial to define, and eventually augment, pulmonary host defense in severe bacterial infections. Dr. Baker’s work is innovative in that she blends in vitro and in vivo studies with immunomodulatory polymers and chimeric mouse models to rigorously study a pathogen (Bps) that poses a severe emerging infectious risk given its potential as a bioweapon and newly confirmed environmental presence in the United States. Dr. Baker is a Senior Fellow in the Division of Allergy and Infectious Diseases at the University of Washington and a physician-scientist with an interest in pulmonary immunology and emerging infectious diseases research. To complement her proposed research goals, Dr. Baker also devised an accompanying Career Development Plan to provide her with advanced research training in microscopy and imaging, innate immunology, immunoengineering, and lung injury. She will collaborate with a multidisciplinary team at the University of Washington that includes experts in pulmonary host defense and bioengineering to provide targeted mentorship for this proposal. By the conclusion of this Award, Dr. Baker will transition to a role as an independent physician- scientist. She will contribute to the scientific community by providing mechanistic insight into the innate immune function of the AM during Gram-negative pulmonary infection and effectively probing these pathways using immunomodulatory polymers.