title: Endogenous interleukin-18 improves the early antimicrobial host response in severe melioidosis.
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.
authors.affiliation: Academic Medical Center, Meibergdreef 9, Room G2-132, 1105 AZ Amsterdam, The Netherlands. w.j.wiersinga@amc.uva.nl
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
authors.forename: Gerritje J W
authors.initials: GJ
authors.lastname: van der Windt
authors.forename: Anita
authors.initials: A
authors.lastname: de Boer
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Arjen
authors.initials: A
authors.lastname: Dondorp
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Day
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001769:Blood / Q000382:microbiology; D016957:Burkholderia pseudomallei / Q000276:immunology*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000276:immunology; D020382:Interleukin-18 / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000382:microbiology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008297:Male; D008554:Melioidosis / Q000276:immunology* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D013785:Thailand
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; C118370:interleukin-18 binding protein