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THERAPEUTIC ADMINISTRATION OF A MONOCLONAL ANTI-IL-1Β ANTIBODY PROTECTS AGAINST EXPERIMENTAL MELIOIDOSIS

Weehuizen, T and Lankelma, J and de Jong, K and de Boer, O and Roelofs, J and Day, N and Gram, Hermann and de vos, j and Wiersinga, J (2016) THERAPEUTIC ADMINISTRATION OF A MONOCLONAL ANTI-IL-1Β ANTIBODY PROTECTS AGAINST EXPERIMENTAL MELIOIDOSIS. Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal of the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies., 46. pp. 566-574. ISSN 1540-0514

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 plays a crucial role in the host defense and its downstream product interleukin-1 beta (IL-1β) has been proposed to play a harmful role in melioidosis.

Methods
Caspase-1, NLRP3 and ASC expression was determined in leukocytes of melioidosis patients. Wild-type (WT), NLRP3-deficient (Nlrp3-/-) and Asc-/- mice were infected with B.pseudomallei. Additionally, WT mice were treated with an anti-IL-1β antibody. Endpoint parameters included bacterial loads, inflammation, pathology and survival.

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 24h post-infection still protected mice against 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.

Item Type: Article
Date Deposited: 15 Feb 2017 00:45
Last Modified: 15 Feb 2017 00:45
URI: https://oak.novartis.com/id/eprint/24302

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