Impaired Early Cytokine Responses at the Site of Infection in a Murine Model of Type 2 Diabetes and Melioidosis Comorbidity

Hodgson, Kelly; Govan, Brenda; Walduck, Anna; Ketheesan, Natkunam; Morris, Jodie L.

doi:10.1128/iai.00930-12

Cited by 32 publications

(36 citation statements)

References 45 publications

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“…However, it is not feasible to confirm whether reduced IL-8 production could influence migration of PMNs to infected foci or not in human patients. Therefore, we propose that reduced IL-1β and IL-8 axis, which is a strong activator of PMN functions, may result in impaired activation of PMNs at the infection site, and reduced bacterial killing as suggested in the diabetic mouse model33. These suggestions are consistent with the evidence in humans shown that diabetes is the most common underlying condition associated with melioidosis4.…”

Section: Discussionsupporting

confidence: 86%

Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection

Kewcharoenwong

Rinchai

Utispan

et al. 2013

Sci Rep

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Type 2 diabetes mellitus is a major risk factor for melioidosis, which is caused by Burkholderia pseudomallei. Our previous study has shown that polymorphonuclear neutrophils (PMNs) from diabetic subjects exhibited decreased functions in response to B. pseudomallei. Here we investigated the mechanisms regulating cytokine secretion of PMNs from diabetic patients which might contribute to patient susceptibility to bacterial infections. Purified PMNs from diabetic patients who had been treated with glibenclamide (an ATP-sensitive potassium channel blocker for anti-diabetes therapy), showed reduction of interleukin (IL)-1β and IL-8 secretion when exposed to B. pseudomallei. Additionally, reduction of these pro-inflammatory cytokines occurred when PMNs from diabetic patients were treated in vitro with glibenclamide. These findings suggest that glibenclamide might be responsible for the increased susceptibility of diabetic patients, with poor glycemic control, to bacterial infections as a result of its effect on reducing IL-1β production by PMNs.

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Section: Discussionsupporting

confidence: 86%

Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection

Kewcharoenwong

Rinchai

Utispan

et al. 2013

Sci Rep

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“…Hodgson et al report increased mortality from subcutaneous B. pseudomallei infection in a murine model of diabetes (BKS.Cg-Dock7(m)+/+Lepr(db)/J mice), and found a defect in intracellular killing by peritoneal macrophages taken from diabetic animals compared to non-diabetic animals [9]. The reason behind the increased susceptibility in diabetes is unclear, but may relate to delayed or reduced cytokine production in diabetes [7], [8], [41].…”

Section: Discussionmentioning

confidence: 99%

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

et al. 2013

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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.

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“…One obvious selective pressure might come from attack by the host’s immune system. Candidate modulators of host immunity in melioidosis might include the TNF-α , IFN-γ , and TLR4 genes, as genetic knockouts of TNF-α and IFN-γ have been shown to increase B. pseudomallei susceptibility in mouse models (12), and genetic variation in Toll-like receptors (TLRs), in particular TLR4 have been associated with host susceptibility to disease (13). However, the impact of these innate immunity pathways on the direct induction of genomic changes in B. pseudomallei remains to be experimentally demonstrated.…”

Section: Genetic Variation During Chronic Melioidosismentioning

confidence: 99%

Less Is More: Burkholderia pseudomallei and Chronic Melioidosis

Nandi

Tan

2013

mBio

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The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a serious infectious disease of humans and animals. Once considered an esoteric tropical disease confined to Southeast Asia and northern Australia, research on B. pseudomallei has recently gained global prominence due to its classification as a potential bioterrorism agent by countries such as the United States and also by increasing numbers of case reports from regions where it is not endemic. An environmental bacterium typically found in soil and water, assessing the true global prevalence of melioidosis is challenged by the fact that clinical symptoms associated with B. pseudomallei infection are extremely varied and may be confused with diverse conditions such as lung cancer, tuberculosis, or Staphyloccocus aureus infection. These diagnostic challenges, coupled with lack of awareness among clinicians, have likely contributed to underdiagnosis and the high mortality rate of melioidosis, as initial treatment is often either inappropriate or delayed. Even after antibiotic treatment, relapses are frequent, and after resolution of acute symptoms, chronic melioidosis can also occur, and the symptoms can persist for months to years. In a recent article, Price et al. [mBio 4(4):e00388-13, 2013, doi:10.1128/mBio.00388-13] demonstrate how comparative genomic sequencing can reveal the repertoire of genetic changes incurred by B. pseudomallei during chronic human infection. Their results have significant clinical ramifications and highlight B. pseudomallei’s ability to survive in a wide range of potential niches within hosts, through the acquisition of genetic adaptations that optimize fitness and resource utilization.

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Impaired Early Cytokine Responses at the Site of Infection in a Murine Model of Type 2 Diabetes and Melioidosis Comorbidity

Cited by 32 publications

References 45 publications

Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection

Glibenclamide reduces pro-inflammatory cytokine production by neutrophils of diabetes patients in response to bacterial infection

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

Less Is More: Burkholderia pseudomallei and Chronic Melioidosis

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