Role of the glucose-6-phosphate translocase on bacterial handling in human macrophages

Thesis

Disruption of the homeostatic balance in the intestine of genetically susceptible individuals can lead to inflammatory bowel disease (IBD), such as Crohn's disease (CD) or ulcerative colitis (UC). Defects in glucose-6-phosphate metabolism due to defects in glucose-6-phosphatase or glucose-6-phosphate translocase cause a rare Mendelian form of congenital neutropenia and CD like intestinal inflammation. The aim of this project is to investigate the mechanisms by which defective metabolism in macrophages might cause CD like intestinal inflammation via defective bacterial handling. We used a chemical inhibitor model to study the effect of glucose-6-phosphate-translocase inhibition in macrophages using a cholorogenic acid derivative. Defective glucose-6-phosphate translocase caused a reduction in bactericidal activity by changing the metabolism in macrophages and polarising them to M1 phenotype via the mTOR signalling pathway. Blockade of mTOR using rapamycin reversed the defective bacterial handling in macrophages with defective glucose-6-phosphatase enzyme. This study provides a link between metabolic defect and immune-mediated colitis that is associated with macrophage dysfunction. This might have therapeutic implications for subgroups of patients with intestinal inflammation.

Authors: Balagopal, K

• DOI: 10.5287/ora-8j94mkzer
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Keywords: G6PT; macrophages; IBD; CD