Abstract
Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. The interaction of B. pseudomallei with the inflammasome and the role of pyroptosis, IL-1β, and IL-18 during melioidosis have not been investigated in detail. Here we show that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 and are critical for inflammasome-mediated resistance to melioidosis. In vitro production of IL-1β by macrophages or dendritic cells infected with B. pseudomallei was dependent on NLRC4 and NLRP3 while pyroptosis required only NLRC4. Mice deficient in the inflammasome components ASC, caspase-1, NLRC4, and NLRP3, were dramatically more susceptible to lung infection with B. pseudomallei than WT mice. The heightened susceptibility of Nlrp3-/- mice was due to decreased production of IL-18 and IL-1β. In contrast, Nlrc4-/- mice produced IL-1β and IL-18 in higher amount than WT mice and their high susceptibility was due to decreased pyroptosis and consequently higher bacterial burdens. Analyses of IL-18-deficient mice revealed that IL-18 is essential for survival primarily because of its ability to induce IFNγ production. In contrast, studies using IL-1RI-deficient mice or WT mice treated with either IL-1β or IL-1 receptor agonist revealed that IL-1β has deleterious effects during melioidosis. The detrimental role of IL-1β appeared to be due, in part, to excessive recruitment of neutrophils to the lung. Because neutrophils do not express NLRC4 and therefore fail to undergo pyroptosis, they may be permissive to B. pseudomallei intracellular growth. Administration of neutrophil-recruitment inhibitors IL-1ra or the CXCR2 neutrophil chemokine receptor antagonist antileukinate protected Nlrc4-/- mice from lethal doses of B. pseudomallei and decreased systemic dissemination of bacteria. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1β.
Highlights
The ability to detect infection by pathogenic microbes and to restrict their growth are fundamental for the wellbeing of multicellular organisms
We examined the interaction of B. pseudomallei with the inflammasome, an important innate immune pathway that regulates at least two host responses protective against infections: 1) secretion of the proinflammatory cytokines IL-1b and IL-18 and 2) induction of pyroptosis, a form of cell death that restricts intracellular bacteria growth
Using a mouse model of melioidosis we show that two distinct inflammasomes are activated by B. pseudomallei infection
Summary
The ability to detect infection by pathogenic microbes and to restrict their growth are fundamental for the wellbeing of multicellular organisms. Pattern recognition receptors, including the Toll-like receptor (TLR) and the NLR, recognize microbial products and ‘‘danger signals’’ released by stressed cells and, in turn, activate signaling pathways that initiate the inflammatory response and regulate development of adaptive immunity. Activation of caspase-1 in the context of the inflammasome is responsible for the proteolytic processing of the immature forms of IL-1b and IL-18, a modification required for the secretion and bio-activity of these proinflammatory cytokines. Activation of caspase-1 triggers a form of cell death, known as pyroptosis, that effectively restricts intracellular bacterial growth [2,3]. NLRP3 controls caspase-1 activation in response to ‘‘danger signals’’, several particles and crystals, and various bacteria, virus, and fungi. The NLRC4 inflammasome is responsive to a narrower spectrum of activators including cytoplasmically delivered bacterial flagellin and the basal rod constituent of various bacterial Type III secretion systems (T3SS).
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