Endogenous interleukin-18 improves the early antimicrobial host response in severe melioidosis.
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.
Wiersinga
W Joost
WJ
Academic Medical Center, Meibergdreef 9, Room G2-132, 1105 AZ Amsterdam, The Netherlands. w.j.wiersinga@amc.uva.nl
Wieland
Catharina W
CW
van der Windt
Gerritje J W
GJ
de Boer
Anita
A
Florquin
Sandrine
S
Dondorp
Arjen
A
Day
Nicholas P
NP
Peacock
Sharon J
SJ
van der Poll
Tom
T
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
D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; C118370:interleukin-18 binding protein