Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis. Issue 5 (November 2016)

• Record Type: Journal Article
• Authors: Weehuizen, Tassili A. F.; Lankelma, Jacqueline M.; De Jong, Hanna K.; De Boer, Onno J.; Roelofs, Joris J. T. H.; Day, Nicholas P.; Gram, Hermann; De Vos, Alex F.; Wiersinga, W. Joost
• Is Part Of: Shock. Volume 46:Issue 5(2016:Nov.)
• Publication Date: 2016-11
• Subjects: Anti-interleukin-1β -- ASC -- Burkholderia pseudomallei -- melioidosis -- NLRP3 -- sepsis; Shock -- Periodicals; Shock -- Periodicals; Choc (Pathologie) -- Périodiques; Shock; Periodicals; 616.0475
• DOI: 10.1097/SHK.0000000000000625
• Languages: English
• ISSNs: 1073-2322

Abstract

ABSTRACT: 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 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. Abstract : Supplemental Digital Content is available in the text