Contribution of glucose to increased respiratory bacterial burden in hyperglycaemia
File(s)
Author(s)
Gill, Simren Kaur
Type
Thesis
Abstract
It has recently been proposed that uncontrolled hyperglycaemia in people with diabetes increases lung glucose, so providing a richer growth medium facilitating bacterial infection. Where diabetes is controlled, there is a reduced associated risk of bacterial infection. The aim of this thesis was to determine the effect of glucose on bacterial growth in vivo and directly link bacterial glucose metabolism with increased respiratory tract bacterial load in hyperglycaemia. P. aeruginosa, a Gram-negative opportunistic pathogen, which is a major cause of respiratory infections, was used as chronic P. aeruginosa infections are most commonly associated with people with cystic fibrosis (CF) and chronic obstructive pulmonary diseases (COPD), but importantly P. aeruginosa is increasingly diagnosed in diabetic patients with pneumonia/lung infection. To test the hypothesis, P. aeruginosa mutants were generated by deleting oprB, gltK, gtrS and glk genes and these mutant strains were used in in vitro and in vivo infection models developed during this thesis. The
mutants had drastically reduced growth in minimal medium containing glucose as the sole carbon source, whereas they were unaltered when grown in rich medium. In order to explore the effect of elevated glucose with minimal effects on the immune response, streptozocin was used to induce diabetes, instead of genetically obese mice, which have a complex phenotype and impaired immune responses. Streptozocin induced hyperglycaemia also led to increased bacterial load in the airways when mice were infected with wild type PAO1 but not with the glucose
uptake and metabolism mutants. To further support this hypothesis when metformin was used to lower glucose levels it resulted in a reduced bacterial burden.
mutants had drastically reduced growth in minimal medium containing glucose as the sole carbon source, whereas they were unaltered when grown in rich medium. In order to explore the effect of elevated glucose with minimal effects on the immune response, streptozocin was used to induce diabetes, instead of genetically obese mice, which have a complex phenotype and impaired immune responses. Streptozocin induced hyperglycaemia also led to increased bacterial load in the airways when mice were infected with wild type PAO1 but not with the glucose
uptake and metabolism mutants. To further support this hypothesis when metformin was used to lower glucose levels it resulted in a reduced bacterial burden.
Version
Open Access
Date Issued
2016-12
Date Awarded
2017-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Tregoning, John
Filloux, Alain
Sponsor
Wellcome Trust (London, England)
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)