E-Thesis 60 views 26 downloads
Methods to Identify Biomarkers to Predict Bacterial Sepsis / Heather Chick
Swansea University Author: Heather Chick
DOI (Published version): 10.23889/SUthesis.67940
Abstract
Bacterial sepsis represents a significant challenge for clinicians worldwide and causes 11 million deaths annually worldwide. In Wales, Escherichia coli and Staphylococcus species are the predominant causes. Predicting sepsis accurately is complicated by the multifactorial nature of the disorder res...
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Swansea, Wales, UK
2020
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Wilkinson, Thomas S. |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa67940 |
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| Abstract: |
Bacterial sepsis represents a significant challenge for clinicians worldwide and causes 11 million deaths annually worldwide. In Wales, Escherichia coli and Staphylococcus species are the predominant causes. Predicting sepsis accurately is complicated by the multifactorial nature of the disorder resulting in very few useful biomarkers. This thesis aimed to characterise the immunological and cellular response to model and pathogenic bacteria and analyse the genomic composition of clinically relevant extraintestinal blood culture-positive E. coli. Eight strains comprising E. coli, S. aureus and S. epidermidis were applied to a whole blood infection model, incubated for up to eight hours and the supernatant used in ELISA, flow cytometry and mass spectrometry analysis. Clinically relevant E. coli were obtained from the Hywel Dda University Health Board in West Wales and submitted for DNA sequencing and whole genome analysis using the pan-genome pipeline Roary. E. coli induced significantly more IL-6, MIP-1α and MIP-3α and significantly less phagocytosis than that induced by both Staphylococcus species. Flow cytometry analysis of leukocyte subsets revealed a robust infection model that confirmed interactions seen in the blood were due to infection, and a loss of CD14 was characterised on the monocytes treated with bacteria. The oxysterol 25-HC was confirmed to be significantly elevated in blood treated with E. coli which challenges the previous dogma of virus restricted induction. Finally, blood culture-positive E. coli were found to be from a diverse range of sequence types and possessed virulence factors and antibiotic resistance genes in abundance. The genes tufA and tufB were found to be significantly associated with sepsis and certain origins of infection. The work undertaken in this thesis identifies biomarkers to predict bacterial sepsis that can be taken forward for clinical validation. |
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| Item Description: |
ORCiD identifier: https://orcid.org/0000-0002-5387-003X |
| Keywords: |
Sepsis, whole blood model, E. coli, S. aureus, S. epidermidis, 25-hydroxycholesterol, bacteraemia |
| College: |
Faculty of Medicine, Health and Life Sciences |