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首页> 外文期刊>Bioengineering >Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7
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Construction and Experimental Validation of a Quantitative Kinetic Model of Nitric Oxide Stress in Enterohemorrhagic Escherichia coli O157:H7

机译：肠出血性大肠杆菌O157：H7中一氧化氮应激定量动力学模型的构建和实验验证

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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.
机译：肠出血性大肠杆菌（EHEC）导致大出血性结肠炎的爆发，由于释放志贺样毒素（Stx），它可能发展为威胁生命的溶血性​​尿毒症综合征（HUS）。先前发现功能性一氧化氮（NO·）还原酶（NorV）可以保护EHEC免受免疫细胞产生的NO·的影响，与高HUS发生率相关，并且表明NorV活性可以延长EHEC的存活时间并增加巨噬细胞内的Stx产生。为了能够定量研究EHEC NO·防御并促进NO·增强疗法的发展，我们翻译了现有的大肠杆菌K-12 NO·对EHEC O157：H7菌株反应的动力学模型。为此，我们在EHEC文化中对[NO·]和[O 2]的测量值训练了不确定的模型参数，使用马尔可夫链蒙特卡罗方法评估了参数和预测的不确定性，并通过以下方法确认了模型的预测准确性：来自缺乏NorV或Hmp（NO·双加氧酶）的基因突变体的实验数据。总体而言，这些结果建立了将模型生物中NO·胁迫的定量模型转化为致病性亚种的方法，这是将这些模型应用于传染病研究的关键步骤。

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