The effect of glibenclamide on the pathogenesis of melioidosis
Koh, Gavin Christian Kia Wee
Peacock, Sharon Jayne
University of Cambridge
Department of Medicine
The Wellcome Trust Sanger Institute
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Koh, G. C. K. W. (2012). The effect of glibenclamide on the pathogenesis of melioidosis (doctoral thesis).
Melioidosis is an important cause of community-acquired sepsis, endemic to Southeast Asia and Northern Australia. Melioidosis is caused by the soil saprophyte, Burkholderia pseudomallei, a motile Gram-negative bacillus, and is associated with a mortality rate that approaches 50% in Northeast Thailand. The most important risk factor for melioidosis is diabetes mellitus, and two-thirds of all adult patients with melioidosis have diabetes as a risk factor. It has been noted previously, however, that patients with diabetes have lower mortality than patients without diabetes. In this dissertation, we look at a cohort of 1160 consecutive adult melioidosis patients presenting to Sappasithiprasong Hospital in Ubon Ratchathani, Thailand, 410 (35%) of whom were diagnosed with diabetes prior to admission. We confirmed previous findings that diabetes protected from mortality in melioidosis, but also found that this protective effect was confined to a smaller subset of patients (208 patients) who were treated with glibenclamide prior to admission. Patients with hyperglycaemia (but no diagnosis of diabetes prior to admission) had the same mortality rate as patients without diabetes. In vitro experiments found no inhibitory effect of glibenclamide on bacterial growth, and we therefore looked for evidence of an effect of glibenclamide on the host. We conducted a gene expression study of circulating blood leukocytes in melioidosis patients and compared them to uninfected controls. In this study, we found that glibenclamide was associated with an anti-inflammatory effect on the host response to melioidosis. To further elucidate a mechanism for the action of glibenclamide, we studied the effect of glibenclamide therapy in a mouse model of melioidosis and found that the effect of glibenclamide was specific to interleukin-1β secretion. This reduction in interleukin-1β secretion was associated with reduced cellular influx into the lungs as well as lower bacterial loads in blood, liver and spleen.
Glibenclamide, Melioidosis, Burkholderia pseudomallei, Diabetes mellitus, Interleukin-1 beta
This work was supported by the Wellcome Trust [grant number 086532/Z/08/Z]
This record's URL: http://www.dspace.cam.ac.uk/handle/1810/242187
Attribution-NonCommercial-NoDerivs 2.0 UK: England & Wales, The effect of diabetes mellitus and glibenclamide on the pathogenesis of melioidosis. Copyright © 2009–2011 Gavin Christian Kia Wee Koh Permission is granted to copy, distribute and/or modify this document under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 2.0 UK: England & Wales Licence, provided this work is properly cited. A copy of the licence is included in the section entitled “Creative Commons Licence”. A copy of the licence is also available at http://creativecommons.org/licenses/by-nc-sa/2.0/uk/legalcode.
Licence URL: http://creativecommons.org/licenses/by-nc-nd/2.0/uk/
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