Caspase-1 inflammasome activity in patients with Staphylococcus aureus bacteremia.

The inflammasome is a multiprotein complex that mediates caspase-1 activation with subsequent maturation of the proinflammatory cytokines IL-1ß and IL-18. The NLRP3 inflammasome is known to be activated by Staphylococcus aureus, one of the leading causes of bacteremia worldwide. Inflammasome activation and regulation in response to bacterial infection have been found to be of importance for a balanced host immune response. However, inflammasome signaling in vivo in humans initiated by S. aureus is currently sparsely studied. This study therefore aimed to investigate NLRP3 inflammasome activity in 20 patients with S. aureus bacteremia (SAB), by repeated measurement during the first week of bacteremia, compared with controls. Caspase-1 activity was measured in monocytes and neutrophils by flow cytometry detecting FLICA (fluorescent-labeled inhibitor of caspase-1), while IL-1ß and IL-18 was measured by Luminex and ELISA, respectively. As a measure of inflammasome priming, messenger RNA (mRNA) expression of NLRP3, CASP1 (procaspase-1), and IL1B (pro-IL-1ß) was analyzed by quantitative PCR. We found induced caspase-1 activity in innate immune cells with subsequent release of IL-18 in patients during the acute phase of bacteremia, indicating activation of the inflammasome. There was substantial interindividual variation in caspase-1 activity between patients with SAB. We also found an altered inflammasome priming with low mRNA levels of NLRP3 accompanied by elevated mRNA levels of IL1B. This increased knowledge of the individual host immune response in SAB could provide support in the effort to optimize management and treatment of each individual patient.

Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent.

Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1ß (IL-1ß), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanism-priming and licensing of inflammasome activation-but there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1ß release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.