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Understanding the role of glucose metabolism during macrophage challenge with Streptococcus pneumoniae

Fisk, Emily (2018) Understanding the role of glucose metabolism during macrophage challenge with Streptococcus pneumoniae. PhD thesis, University of Sheffield.

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Abstract

In 2015, the WHO recorded lower respiratory infections as the leading cause of mortality by infection worldwide (World Health Organization 2017). Streptococcus pneumoniae is just one bacterial species responsible for this burden. This pathogen is managed through using antibiotics, however it’s recognised that pathogens can rapidly adapt to the selective pressure of antibiotics and acquire resistant mechanisms. Therefore, as the affliction of AMR grows wider, alternative treatments for bacterial infections are urgently required. One suggested method involves the development of host-based therapies. This requires a thorough understanding of host-pathogen interactions, to appropriately control host immune responses without causing excessive inflammation or host damage. This is particularly important for bacteria such as S. pneumoniae, which frequently colonise hosts without causing serious disease. Metabolism has emerged as a key regulator of innate immune responses, particularly macrophages activated with the bacterial component LPS (O’Neill et al. 2016); however, few studies have sought to uncover the importance of metabolism during macrophage challenge with live bacteria. Therefore, the work reported herein aimed to understand how S. pneumoniae modulates murine macrophage metabolism, with a view to honing host responses to improve infection outcome, as a potential alternative to antibiotics. This thesis outlines the optimisation and use of Seahorse XF Analysis and NMR Spectroscopy, to understand changes in macrophage metabolism, following stimulation with S. pneumoniae compared to the pro-inflammatory macrophage stimulus LPS. I have also addressed the use of glycolytic inhibitors, to probe the importance of glucose metabolism in regulating macrophage effector functions, such as phagocytosis and cytokine release. My principal finding is that S. pneumoniae does not induce the same metabolic changes as recorded for LPS in the literature. I propose that bacterial stimulation induces distinct macrophage activation phenotypes that depend on tailored host-pathogen interactions, which are likely to be unique for different pathogens of interest.

Item Type: Thesis (PhD)
Keywords: host-pathogen interaction; NMR Spectroscopy; Seahorse; metabolism; BMDM; S. pneumoniae;
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.774002
Depositing User: Miss Emily Fisk
Date Deposited: 13 May 2019 08:36
Last Modified: 25 Sep 2019 20:07
URI: http://etheses.whiterose.ac.uk/id/eprint/23872

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