Mechanisms of Ferritin-iron Acquisition and Burkholderia pseudomallei Infection.

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DESCRIPTION (provided by applicant): Burkholderia pseudomallei (Bp) is an emerging Gram-negative bacterial pathogen that is found with increasing frequency in tropical and subtropical regions of the world. The bacterium causes melioidosis, a disease comprising difficult-to-treat infections ranging from acute sepsis to long-lasting chronic manifestations. Our knowledge of the arsenal of factors that allow Bp to invade, spread and survive in the host is stil rudimentary at best, and virtually nothing is known about iron acquisition pathways crucial for bacterial survival. Previously it was assumed that the organism employs iron-acquisition systems commonly found in other Gram-negative bacterial pathogens, but our preliminary data indicate that Bp may employ a ferritin-iron acquisition pathway. The studies proposed here are intended to elucidate a critical pathway required for the pathogenesis of this emerging pathogen. First, we will assess whether access to ferritin-iron involves proteolytic degradation of the ferritin scaffold. Second, we will obtain evidence for existence of a ferritin-iron acquisition pathway by identifying mutants defective in ferritin-iron transport. Third, we will investigate in vivo requirements for ferritin-iron acquisition genes using cell culture and mouse models. Results from these investigations will substantially alter our current view of iron acquisition mechanisms in pathogenic Gram-negative bacteria and also provide a more complete picture of the pathogenesis of infection with Bp.