Tassili A.F. WeehuizenJacqueline M. LankelmaHanna K. De JongOnno J. De BoerJoris J.T.H. RoelofsNicholas P. DayHermann GramAlex F. De VosW. Joost WiersingaAcademic Medical Centre, University of AmsterdamMahidol UniversityNuffield Department of Clinical MedicineNovartis International AG2018-12-112019-03-142018-12-112019-03-142016-10-01Shock. Vol.46, No.5 (2016), 566-57415400514107323222-s2.0-84970002344https://repository.li.mahidol.ac.th/handle/123456789/41122Copyright © 2016 by the Shock Society. 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 componentswas 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 WTmice 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 postinfection 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.Mahidol UniversityMedicineArticleSCOPUS10.1097/SHK.0000000000000625