Redox-Mediated Inactivation of the Transcriptional Repressor RcrR is Responsible for Uropathogenic Escherichia coli's Increased Resistance to Reactive Chlorine Species.
Redox-Mediated Inactivation of the Transcriptional Repressor RcrR is Responsible for Uropathogenic Escherichia coli's Increased Resistance to Reactive Chlorine Species.
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克服压力环境的能力对于病原体在宿主体内的生存至关重要。细菌面临的一项挑战是接触活性氯物质 (RCS)，它是由先天免疫细胞产生的，是氧化爆发的关键部分。次氯酸 (HOCl) 是最有效的抗菌 RCS，与被吞噬的病原体中的广泛大分子损伤有关。然而，细菌已经进化出防御策略来减轻次氯酸介导的损伤的影响。其中包括 RCS 感应转录调节因子，可在非胁迫和 HOCl 胁迫下控制 HOCl 保护基因的表达。尿路致病性大肠杆菌 (UPEC) 是尿路感染 (UTI) 的主要病原体，在发病过程中特别容易接触浸润性中性粒细胞；然而，它们对次氯酸的反应和防御仍未完全被探索。在这里，我们提供的证据表明，与其他大肠杆菌相比，UPEC 菌株能够耐受更高水平的 HOCl，并且能够更好地免受中性粒细胞介导的杀伤。 HOCl胁迫的 UPEC 的转录组分析揭示了由三个基因组成的操纵子的上调，其中一个基因编码转录调节因子 RcrR。我们将 RcrR 鉴定为 HOCl 响应性转录阻遏蛋白，在非应激条件下，它与操纵基因结合并抑制其靶基因的表达。然而，在 HOCl 暴露期间，阻遏物形成可逆的分子间二硫键并从 DNA 解离，导致操纵子的去阻遏。删除其中一个靶基因使 UPEC 显着更容易受到 HOCl 和吞噬作用的影响，表明 HOCl 介导的调节子诱导在 UPEC 的 HOCl 抗性中起主要作用。
The ability to overcome stressful environments is critical for pathogen survival in the host. One challenge for bacteria is the exposure to reactive chlorine species (RCS), which are generated by innate immune cells as a critical part of the oxidative burst. Hypochlorous acid (HOCl) is the most potent antimicrobial RCS and is associated with extensive macromolecular damage in the phagocytized pathogen. However, bacteria have evolved defense strategies to alleviate the effects of HOCl-mediated damage. Among these are RCS-sensing transcriptional regulators that control the expression of HOCl-protective genes under non-stress and HOCl stress. Uropathogenic Escherichia coli (UPEC), the major causative agent of urinary tract infections (UTIs), is particularly exposed to infiltrating neutrophils during pathogenesis; however, their responses to and defenses from HOCl are still completely unexplored. Here, we present evidence that UPEC strains tolerate higher levels of HOCl and are better protected from neutrophil-mediated killing compared with other E. coli. Transcriptomic analysis of HOCl-stressed UPEC revealed the upregulation of an operon consisting of three genes, one of which encodes the transcriptional regulator RcrR. We identified RcrR as a HOCl-responsive transcriptional repressor, which, under non-stress conditions, is bound to the operator and represses the expression of its target genes. During HOCl exposure, however, the repressor forms reversible intermolecular disulfide bonds and dissociates from the DNA resulting in the derepression of the operon. Deletion of one of the target genes renders UPEC significantly more susceptible to HOCl and phagocytosis indicating that the HOCl-mediated induction of the regulon plays a major role for UPEC’s HOCl resistance.
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