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Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7
Enterohemorrhagic Escherichia coli (EHEC) are responsible for large outbreaks of hemorrhagic colitis, which can progress to life-threatening hemolytic uremic syndrome (HUS) due to the release of Shiga-like toxins (Stx). The presence of a functional nitric oxide (NO·) reductase (NorV), which protects...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597167/ https://www.ncbi.nlm.nih.gov/pubmed/28952571 http://dx.doi.org/10.3390/bioengineering3010009 |
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author | Robinson, Jonathan L. Brynildsen, Mark P. |
author_facet | Robinson, Jonathan L. Brynildsen, Mark P. |
author_sort | Robinson, Jonathan L. |
collection | PubMed |
description | Enterohemorrhagic Escherichia coli (EHEC) are responsible for large outbreaks of hemorrhagic colitis, which can progress to life-threatening hemolytic uremic syndrome (HUS) due to the release of Shiga-like toxins (Stx). The presence of a functional nitric oxide (NO·) reductase (NorV), which protects EHEC from NO· produced by immune cells, was previously found to correlate with high HUS incidence, and it was shown that NorV activity enabled prolonged EHEC survival and increased Stx production within macrophages. To enable quantitative study of EHEC NO· defenses and facilitate the development of NO·-potentiating therapeutics, we translated an existing kinetic model of the E. coli K-12 NO· response to an EHEC O157:H7 strain. To do this, we trained uncertain model parameters on measurements of [NO·] and [O(2)] in EHEC cultures, assessed parametric and prediction uncertainty with the use of a Markov chain Monte Carlo approach, and confirmed the predictive accuracy of the model with experimental data from genetic mutants lacking NorV or Hmp (NO· dioxygenase). Collectively, these results establish a methodology for the translation of quantitative models of NO· stress in model organisms to pathogenic sub-species, which is a critical step toward the application of these models for the study of infectious disease. |
format | Online Article Text |
id | pubmed-5597167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-55971672017-09-21 Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 Robinson, Jonathan L. Brynildsen, Mark P. Bioengineering (Basel) Article Enterohemorrhagic Escherichia coli (EHEC) are responsible for large outbreaks of hemorrhagic colitis, which can progress to life-threatening hemolytic uremic syndrome (HUS) due to the release of Shiga-like toxins (Stx). The presence of a functional nitric oxide (NO·) reductase (NorV), which protects EHEC from NO· produced by immune cells, was previously found to correlate with high HUS incidence, and it was shown that NorV activity enabled prolonged EHEC survival and increased Stx production within macrophages. To enable quantitative study of EHEC NO· defenses and facilitate the development of NO·-potentiating therapeutics, we translated an existing kinetic model of the E. coli K-12 NO· response to an EHEC O157:H7 strain. To do this, we trained uncertain model parameters on measurements of [NO·] and [O(2)] in EHEC cultures, assessed parametric and prediction uncertainty with the use of a Markov chain Monte Carlo approach, and confirmed the predictive accuracy of the model with experimental data from genetic mutants lacking NorV or Hmp (NO· dioxygenase). Collectively, these results establish a methodology for the translation of quantitative models of NO· stress in model organisms to pathogenic sub-species, which is a critical step toward the application of these models for the study of infectious disease. MDPI 2016-02-06 /pmc/articles/PMC5597167/ /pubmed/28952571 http://dx.doi.org/10.3390/bioengineering3010009 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Robinson, Jonathan L. Brynildsen, Mark P. Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 |
title | Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 |
title_full | Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 |
title_fullStr | Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 |
title_full_unstemmed | Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 |
title_short | Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7 |
title_sort | construction and experimental validation of a quantitative kinetic model of nitric oxide stress in enterohemorrhagic escherichia coli o157:h7 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597167/ https://www.ncbi.nlm.nih.gov/pubmed/28952571 http://dx.doi.org/10.3390/bioengineering3010009 |
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