The purpose of this Program Project is to enhance basic knowledge at the molecular level of host-pathogen relationships, focusing on macrophages, dendritic cells and their products, with respect to 3 bacterial pathogens, their products and their mechanisms of evasion or repair-- Mycobacterium tuberculosis (Mtb), Bacillus anthracis (Ba) and Yersinia pestis (Yp)-- and to use this knowledge to develop translational approaches to novel chemotherapeutics and vaccines. Mtb, Ba and Yp were chosen for study because (i) they allow us to compare and contrast different consequences of bacterial interaction with macrophages and DC; (ii) in each case, those interactionslwhether positive or negative---are critical to the pathogenesis of the disease; (iii) bronchopulmonary macrophages and DC often play a key role in the initial encounter of the host with these pathogens; and (iv) these pathogens use diverse mechanisms to evade or repair the antimicrobial lesions inflicted on them by host macrophages and DC. Specifically, this Program explores how human bronchopulmonary macrophages respond to Ba spores and toxins at the level of gene expression; how we can develop new inhibitors of enzymes within Mtb and Yp that are critical to the pathogenesis of their infections, namely, enzymes that degrade oxidized or nitrosated proteins and synthesize siderophores; and how we can use gene therapy vectors to target exogenous antigen into the appropriate compartments of DC to induce an effective vaccine against Yp while simultaneously providing for short term passive immunity. Cores provide for BSL3 wet lab and mouse work; microarray analysis of gene expression; computation and comparison of gene expression results; and high throughput screening of chemical libraries.
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