BACKGROUND:: Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3-inflammasome and its downstream product interleukin-1 beta (IL-1β) have been proposed to play crucial roles in melioidosis. In this study we characterized the role of IL-1β more closely and we assessed its therapeutic potential. METHODS:: mRNA expression of inflammasome components was determined in isolated leukocytes of 32 healthy controls and 34 patients with sepsis caused by B. pseudomallei.Wild-type (WT), NLRP3-deficient (Nlrp3) and Asc mice were infected with B. pseudomallei. In additional experiments, infected WT mice were treated with an anti-IL-1β antibody. After 24, 48 and 72?hours (h) mice were sacrificed and organs were harvested. Furthermore, survival studies were performed. RESULTS:: Patients with melioidosis exhibited lower mRNA levels of caspase-1, NLRP3 and ASC. Bacterial dissemination and organ damage were increased in B. pseudomallei-infected Nlrp3 and Asc mice, together with a reduced pulmonary cell influx. Anti-IL-1β treatment of B. pseudomallei challenged mice resulted in strongly reduced bacterial counts, organ damage and pulmonary granulocyte influx together with reduced mortality. Postponement of anti-IL-1β treatment for 24?h post-infection still protected mice during melioidosis. CONCLUSION:: Expression of caspase-1, NLRP3 and ASC is altered in melioidosis patients. In mice, both NLRP3 and ASC contribute to the host defense against melioidosis. Anti-IL-1β treatment protects mice against B. pseudomallei infection and might be a novel treatment strategy in melioidosis
