Role of inflammasome-dependent cytokine production and neutrophil recruitment during acute lung injury that protects from Burkholderia species infection

Abstract Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. We have recently shown that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 in response to B. pseudomallei infection. Pyroptosis and IL-18 production were equally important for resistance to B. pseudomallei. Surprisingly, IL-1β was found to be deleterious in melioidosis. The detrimental role of IL-1β during melioidosis was due, in part, to excessive recruitment of neutrophils to the lung. We showed that neutrophils do not express NLRC4, fail to undergo pyroptosis, and, therefore, may be permissive to B. pseudomallei intracellular replication leading to increased bacterial burden and morbidity/mortality. Results will be presented to extended the analysis of the role of the inflammasome components NLRP3, NLRC4, ASC, and Caspase-1 and of IL-1β, IL-18, and pyroptosis during lung infection with other Burkholderia species like B. thailandensis and B. cepacia. Preliminary studies indicate that mice that underwent an acute lung injury (ALI) protocol showed an increased resistance to Burkholderia infection. We will show results that characterize the role of IFNγ and neutrophils recruitment in the protective effect of ALI.