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Methods to Identify Biomarkers to Predict Bacterial Sepsis / Heather Chick

Swansea University Author: Heather Chick

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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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Published: Swansea, Wales, UK 2020
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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first_indexed 2024-10-09T09:37:06Z
last_indexed 2024-10-09T09:37:06Z
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spelling v2 67940 2024-10-09 Methods to Identify Biomarkers to Predict Bacterial Sepsis 00e95531dda8486188b1e44f7d27af77 Heather Chick Heather Chick true false 2024-10-09 MEDS 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. E-Thesis Swansea, Wales, UK Sepsis, whole blood model, E. coli, S. aureus, S. epidermidis, 25-hydroxycholesterol, bacteraemia 7 7 2020 2020-07-07 10.23889/SUthesis.67940 ORCiD identifier: https://orcid.org/0000-0002-5387-003X COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Wilkinson, Thomas S. Doctoral Ph.D 2024-10-09T11:01:18.1499637 2024-10-09T10:32:49.7152797 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Heather Chick 1 67940__32562__cead28f1323f4e05aa67eb2a6dc572a2.pdf Chick_Heather_M_PhD_Thesis_Final_Cronfa.pdf 2024-10-09T10:43:28.8881465 Output 5001054 application/pdf E-Thesis – open access true Copyright: The author, Heather Mair Chick, 2020. true eng
title Methods to Identify Biomarkers to Predict Bacterial Sepsis
spellingShingle Methods to Identify Biomarkers to Predict Bacterial Sepsis
Heather Chick
title_short Methods to Identify Biomarkers to Predict Bacterial Sepsis
title_full Methods to Identify Biomarkers to Predict Bacterial Sepsis
title_fullStr Methods to Identify Biomarkers to Predict Bacterial Sepsis
title_full_unstemmed Methods to Identify Biomarkers to Predict Bacterial Sepsis
title_sort Methods to Identify Biomarkers to Predict Bacterial Sepsis
author_id_str_mv 00e95531dda8486188b1e44f7d27af77
author_id_fullname_str_mv 00e95531dda8486188b1e44f7d27af77_***_Heather Chick
author Heather Chick
author2 Heather Chick
format E-Thesis
publishDate 2020
institution Swansea University
doi_str_mv 10.23889/SUthesis.67940
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2020-07-07T11:01:16Z
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score 11.030759

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