Role of neutrophils and elastase in melioidosis



 DESCRIPTION (provided by applicant): Burkholderia pseudomallei (B.p.) is a Gram-negative intracellular bacterium that causes melioidosis, a pneumonic disease endemic to South-East Asia and other tropical regions. B.p. is classified as Tier 1 category B potential bioterrorism agent by the Center for Disease Control and NIAID. B.p. possesses one of the largest bacterial genome characterized so far and horizontal gene transfer, recombination and high mutation rate have been shown to account for the high genome instability and variability observed among clinical isolates and their ability to colonize the host. Using a mouse model of melioidosis, we have recently found that IL-1ß is deleterious in melioidosis. This is very surprising and counterintuitive considering that IL- 1ß is known to be protective against several bacterial and viral infections. Our preliminary data indicate that IL-1ß deleterious effect is due to excessive recruitment of neutrophils to the lung. This, in turn, leads to release of neutrophil elastase causing tissue damage, generation of bradykinin and vascular leakage that determines morbidity and mortality. Taken together, our studies identified neutrophils recruitment and elastase release as potential therapeutic targets for treatment of melioidosis. The goal of our studies is to identify the mechanisms responsible for neutrophils recruitment to the infected lung and understand the basis for the deleterious role of elastase during melioidosis. Pharmacological interventions aimed at inhibiting these pathways will be tested using existing human-tested drugs, a fact that increases the likelihood that our studies will have a rapid translation into the clinic. Our studies will also determine whether differential neutrophil recruitment and elastase release account for different pathogenicity of a panel of B.p. clinical isolates and whether establishment of persistent infection is affected by these pathways. Aim 1: Determine the role of eicosanoids and complement in neutrophil recruitment during melioidosis. Aim 2: Determine the role of neutrophil elastase in the establishment of persistent infection and the generation of bradykinin during acute melioidosis. Aim 3: Test B. pseudomallei clinical isolates for their ability to induce inflammasome activation and cause IL-1ß- and elastase-dependent morbidity and mortality.