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. 2007 Aug;75(8):3739-46.
doi: 10.1128/IAI.00080-07. Epub 2007 May 21.

Endogenous interleukin-18 improves the early antimicrobial host response in severe melioidosis

W Joost Wiersinga  1 , Catharina W Wieland, Gerritje J W van der Windt, Anita de Boer, Sandrine Florquin, Arjen Dondorp, Nicholas P Day, Sharon J Peacock, Tom van der Poll
Affiliations

Endogenous interleukin-18 improves the early antimicrobial host response in severe melioidosis

W Joost Wiersinga et al. Infect Immun. 2007 Aug.

Abstract

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.

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Figures

FIG. 1.
FIG. 1.
Plasma IL-18 and IL-18BP and blood leukocyte IL-18 mRNA levels in patients with culture-proven melioidosis: increased levels of IL-18 in plasma (A), IL-18 mRNA in peripheral blood leukocytes (B), and IL-18 mRNA in peripheral blood monocytes (C) of patients (n = 34) with septic melioidosis compared to healthy controls (n = 32). The strongly increased levels of IL-18BP (D) correlated with IL-18 levels (E). Two asterisks, P < 0.01; three asterisks, P < 0.001. B2M, β2-microglobulin.
FIG. 2.
FIG. 2.
Correlation of IL-18 and IL-18BP levels with outcome in patients with severe melioidosis. Both IL-18 and IL-18BP levels strongly correlated with outcome. Both IL-18 (A) and IL-18BP (B) were strongly upregulated in patients who died in comparison to the patients who survived. Patients (n = 8) who survived after 2 weeks of intensive treatment showed near normalization of IL-18 (C) and IL-18BP (D) levels. Three asterisks, P < 0.001.
FIG. 3.
FIG. 3.
Survival and bacterial outgrowth in IL-18 KO mice infected with B. pseudomallei compared to WT mice. (A) Survival of WT and IL-18 KO mice after intranasal inoculation with B. pseudomallei. Mortality was assessed every 4 h (12 mice per group; the P value indicates the significance of the difference between the groups). (B to D) IL-18 KO mice display strongly increased bacterial loads at 24 and 48 h after infection with B. pseudomallei in the lungs (B) and liver (C) in addition to greater bacterial outgrowth in the spleen (D) and blood (E). The data are means ± SEM (eight mice per group). Two asterisks, P < 0.01; three asterisks, P < 0.001. t, time (in hours).
FIG. 4.
FIG. 4.
Pulmonary inflammation in WT and IL-18 KO mice infected with B. pseudomallei: representative histopathology slides of lungs of WT (A and C) and IL-18 KO (B and D) mice infected with 5 × 102 CFU B. pseudomallei at 24 h (A and B) and 48 h (C and D) after infection. The preparations were stained with hematoxylin and eosin. Original magnification, ×4.
FIG. 5.
FIG. 5.
Liver inflammation in IL-18 KO mice. Livers of IL-18 KO mice showed more inflammation after 48 h than livers of WT mice after inoculation with B. pseudomallei. (A and B) Representative hematoxylin- and eosin-stained liver histology slides for WT (A) and IL-18 KO (B) mice at 48 h after inoculation with 5 × 102 CFU B. pseudomallei. Original magnification, ×4; original magnification for insets, ×20. (C) Pathology scores determined 48 h after inoculation (means ± standard errors) as described in Materials and Methods. (D to F) At 48 h after inoculation IL-18 KO mice also showed enhanced hepatic injury, as reflected by the plasma concentrations of ASAT (D), and more renal failure, as reflected by plasma creatinine (E) and blood urea nitrogen (BUN) (F) levels. The data are the means ± SEM for eight WT mice and eight IL-18 KO mice. U/L, units per liter. An asterisk indicates that the P value is <0.05 for a comparison with the WT control.
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