• Tassili A F Weehuizen, Jacqueline M Lankelma, Hanna K De Jong, Onno J De Boer, Joris J T H Roelofs, Nicholas P Day, Hermann Gram, Alex F De Vos, and W Joost Wiersinga.
• *Center for Infection and Immunity Amsterdam (CINIMA)/Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands †Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands ‡Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand §Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK ||Novartis Institutes for BioMedical Research, Basel, Switzerland ¶Department of Internal medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands.
• Shock. 2016 Nov 1; 46 (5): 566-574.

BackgroundMelioidosis, 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.MethodsmRNA 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.ResultsPatients 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.ConclusionExpression 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.

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