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Infection and Immunity, August 2007, p. 3739-3746, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00080-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Endogenous Interleukin-18 Improves the Early Antimicrobial Host Response in Severe Melioidosis{triangledown}

W. Joost Wiersinga,1,2* Catharina W. Wieland,1,2 Gerritje J. W. van der Windt,1,2 Anita de Boer,1,2 Sandrine Florquin,3 Arjen Dondorp,4 Nicholas P. Day,4,5 Sharon J. Peacock,4,5 and Tom van der Poll1,2

Center for Infection and Immunity Amsterdam (CINIMA),1 Center for Experimental and Molecular Medicine,2 Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands,3 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,4 Center for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom5

Received 13 January 2007/ Returned for modification 8 March 2007/ Accepted 7 May 2007

Melioidosis is caused by the soil saprophyte Burkholderia pseudomallei and is endemic in Southeast Asia. The pathogenesis of melioidosis is still largely unknown, although gamma interferon (IFN-{gamma}) seems to play an obligatory role in host defense. Previously, we have shown that IFN-{gamma} production in melioidosis is controlled in part by interleukin-18 (IL-18). The aim of the present study was to determine the role of IL-18 in the immune response to B. pseudomallei. For this the following investigations were performed. (i) Plasma IL-18 and blood monocyte IL-18 mRNA levels were elevated in 34 patients with culture-proven melioidosis compared to the levels in 32 local healthy controls; in addition, IL-18 binding protein levels were markedly elevated in patients, strongly correlating with mortality. (ii) IL-18 gene-deficient (IL-18 knockout [KO]) mice showed accelerated mortality after intranasal infection with a lethal dose of B. pseudomallei, which was accompanied by enhanced bacterial growth in their lungs, livers, spleens, kidneys, and blood at 24 and 48 h postinfection, compared to wild-type mice. In addition, IL-18 KO mice displayed evidence of enhanced hepatocellular injury and renal insufficiency. Together, these data indicate that the enhanced production of IL-18 in melioidosis is an essential part of a protective immune response to this severe infection.

* Corresponding author. Mailing address: Academic Medical Center, Meibergdreef 9, Room G2-132, 1105 AZ Amsterdam, The Netherlands. Phone: 31-20-5669111. Fax: 31-20-6977192. E-mail: w.j.wiersinga{at}amc.uva.nl

{triangledown} Published ahead of print on 21 May 2007.

Editor: R. P. Morrison

Infection and Immunity, August 2007, p. 3739-3746, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00080-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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