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.MethodsMice (C57BL/6) with streptozocin-induced diabetes were inoculated with ∼6×102 cfu 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).ResultsDiabetic 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.ConclusionsDiabetes 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.
Highlights
Melioidosis is a severe community-acquired sepsis in Southeast Asia, caused by infection with Burkholderia pseudomallei, an environmental soil saprophyte [1]
We show for the first time, in an experimental model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1b secretion, cellular infiltration into the lungs and bacterial dissemination to distant organs
It has been described by multiple authors that killing of intracellular B. pseudomallei by BALB/c mice is deficient compared to C57Bl/6 mice [16,20,21,22,23], and that this failure to clear the bacterium results in continued stimulation of type 1 cytokine secretion [21]
Summary
Melioidosis is a severe community-acquired sepsis in Southeast Asia, caused by infection with Burkholderia pseudomallei, an environmental soil saprophyte [1]. Diabetes is the most commonly identified risk factor for sepsis in general [5] and melioidosis in particular [2], where it occurs in around a third of all melioidosis patients. This is consistent with the fact that diabetes is associated with an impaired host. 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 sought to define the mechanism underlying this observation in a murine model of melioidosis
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