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Identifying Host and Bacterial Biomarkers to Predict Sepsis / MATTHEW LEWIS

Swansea University Author: MATTHEW LEWIS

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DOI (Published version): 10.23889/SUthesis.66753

Abstract

Sepsis is a serious concern for healthcare programmes worldwide and is associated with 11 million deaths annually. E. coli accounts for 20% of bloodstream infections worldwide and is responsible for 17% of sepsis related mortality. Early diagnosis and treatment are critical and delays in initiating...

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Published: Swansea, Wales, UK 2024
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Wilkinson, Thomas S.
URI: https://cronfa.swan.ac.uk/Record/cronfa66753
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first_indexed 2024-06-19T10:00:37Z
last_indexed 2024-06-19T10:00:37Z
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spelling v2 66753 2024-06-19 Identifying Host and Bacterial Biomarkers to Predict Sepsis c97205d77dec650ad7ad09a8560fbf67 MATTHEW LEWIS MATTHEW LEWIS true false 2024-06-19 Sepsis is a serious concern for healthcare programmes worldwide and is associated with 11 million deaths annually. E. coli accounts for 20% of bloodstream infections worldwide and is responsible for 17% of sepsis related mortality. Early diagnosis and treatment are critical and delays in initiating antimicrobial therapy are linked to mortality. Identifying biomarkers to predict patients that might succumb to sepsis is vital to aid in early diagnosis. It was hypothesised that E. coli bacteraemia isolates and isolates from different sources of bacteraemia would elicit a distinctive host response and be genetically unique. Blood culture positive isolates (n=165) were collected from the Hywel Dda University Health Board. Most of the isolates were assigned to the B2 and D phylogroups and belonged to either ST131 or ST73. Antimicrobial resistance in the collection was lower than national averages. Host models of infection were used to identify phenotypic responses of the bacterial collection. IL-8 and MIP3α were increased following stimulation by bacteraemia isolates compared to non-pathogenic strains. Greater IL-8 in whole blood was associated with a urinary and abdominal bacteraemia. Isolates that were resistant to human plasma elicited a higher IL-6, IL-8 and resistin response in whole blood compared to plasma sensitive isolates. Blood culture positive bacteraemia isolates had significantly more virulence factors than control isolates. Bacteraemia isolates expressed more P fimbriae genes. The S fimbrial adhesin genes were found to be significantly different between urinary and abdominal isolates. Abdominal isolates had significantly more sfaC (32%) while urinary isolates had more sfaX (22%). GWAS analysis revealed 6 potential gene targets based on bacterial phenotypes. These were ynbC, yhgE, ybjE, yejF, tufB and yohF. The results contained within this thesis describe new targets for predicting bacteraemia and sepsis and underline the importance of using host and pathogen as sources for biomarkers. E-Thesis Swansea, Wales, UK Sepsis, E. coli, biomarkers, cytokines, bacterial genetics, virulence factors, AMR 29 5 2024 2024-05-29 10.23889/SUthesis.66753 COLLEGE NANME COLLEGE CODE Swansea University Wilkinson, Thomas S. Doctoral Ph.D Health and Care Research Wales Health and Care Research Wales 2024-06-19T11:20:19.9329370 2024-06-19T10:55:18.6047602 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science MATTHEW LEWIS 1 66753__30674__f0a79b607bbd4b2cbd2774b64383cfc4.pdf Lewis_Matthew_L_PhD_Thesis_Final_Redacted_Signature.pdf 2024-06-19T11:06:52.6180397 Output 7575767 application/pdf E-Thesis – open access true Copyright: The Author, Matthew L. Lewis, 2024. true eng
title Identifying Host and Bacterial Biomarkers to Predict Sepsis
spellingShingle Identifying Host and Bacterial Biomarkers to Predict Sepsis
MATTHEW LEWIS
title_short Identifying Host and Bacterial Biomarkers to Predict Sepsis
title_full Identifying Host and Bacterial Biomarkers to Predict Sepsis
title_fullStr Identifying Host and Bacterial Biomarkers to Predict Sepsis
title_full_unstemmed Identifying Host and Bacterial Biomarkers to Predict Sepsis
title_sort Identifying Host and Bacterial Biomarkers to Predict Sepsis
author_id_str_mv c97205d77dec650ad7ad09a8560fbf67
author_id_fullname_str_mv c97205d77dec650ad7ad09a8560fbf67_***_MATTHEW LEWIS
author MATTHEW LEWIS
author2 MATTHEW LEWIS
format E-Thesis
publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUthesis.66753
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
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description Sepsis is a serious concern for healthcare programmes worldwide and is associated with 11 million deaths annually. E. coli accounts for 20% of bloodstream infections worldwide and is responsible for 17% of sepsis related mortality. Early diagnosis and treatment are critical and delays in initiating antimicrobial therapy are linked to mortality. Identifying biomarkers to predict patients that might succumb to sepsis is vital to aid in early diagnosis. It was hypothesised that E. coli bacteraemia isolates and isolates from different sources of bacteraemia would elicit a distinctive host response and be genetically unique. Blood culture positive isolates (n=165) were collected from the Hywel Dda University Health Board. Most of the isolates were assigned to the B2 and D phylogroups and belonged to either ST131 or ST73. Antimicrobial resistance in the collection was lower than national averages. Host models of infection were used to identify phenotypic responses of the bacterial collection. IL-8 and MIP3α were increased following stimulation by bacteraemia isolates compared to non-pathogenic strains. Greater IL-8 in whole blood was associated with a urinary and abdominal bacteraemia. Isolates that were resistant to human plasma elicited a higher IL-6, IL-8 and resistin response in whole blood compared to plasma sensitive isolates. Blood culture positive bacteraemia isolates had significantly more virulence factors than control isolates. Bacteraemia isolates expressed more P fimbriae genes. The S fimbrial adhesin genes were found to be significantly different between urinary and abdominal isolates. Abdominal isolates had significantly more sfaC (32%) while urinary isolates had more sfaX (22%). GWAS analysis revealed 6 potential gene targets based on bacterial phenotypes. These were ynbC, yhgE, ybjE, yejF, tufB and yohF. The results contained within this thesis describe new targets for predicting bacteraemia and sepsis and underline the importance of using host and pathogen as sources for biomarkers.
published_date 2024-05-29T11:20:19Z
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