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Title: Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis
Authors: Gavin C.K.W. Koh
Tassili A. Weehuizen
Katrin Breitbach
Kathrin Krause
Hanna K. de Jong
Liesbeth M. Kager
Arjan J. Hoogendijk
Antje Bast
Sharon J. Peacock
Tom van der Poll
Ivo Steinmetz
W. Joost Wiersinga
Academic Medical Centre, University of Amsterdam
Warwick Medical School
Heartlands Hospital
University of Cambridge
Mahidol University
Keywords: Medicine
Issue Date: 1-Jan-2013
Citation: PLoS Neglected Tropical Diseases. Vol.7, No.10 (2013)
Abstract: Background:Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ~40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide (= glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis.Methods:Mice (C57BL/6) with streptozocin-induced diabetes were inoculated with ∼6×102cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1β by bone-marrow-derived macrophages (BMDM).Results:Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1β production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1β by BMDMs in a dose-dependent fashion.Conclusions:Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1β secretion accompanied by diminished cellular influx and reduced bacterial dissemination to distant organs. We found no evidence for a direct effect of glyburide on the bacterium. © 2013 Koh et al.
ISSN: 19352735
Appears in Collections:Scopus 2011-2015

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