A previously uncharacterized two-component signaling system in uropathogenic Escherichia coli coordinates protection against host-derived oxidative stress with activation of hemolysin-mediated host cell pyroptosis

文献类型： 外文期刊

第一作者： Gu, Hongwei

作者： Gu, Hongwei;Cai, Xuwang;Luo, Jie;Hu, Xiao;Li, Ganwu;Gu, Hongwei;Zhang, Xiaoyang;Cai, Xuwang;Zhang, Xinyang;Cai, Wentong;Li, Ganwu

作者机构：

期刊名称：PLOS PATHOGENS （ 影响因子：6.823； 五年影响因子：7.455 ）

ISSN： 1553-7366

年卷期： 2021 年 17 卷 10 期

页码：

收录情况： SCI

摘要： Uropathogenic Escherichia coli (UPEC) deploy an array of virulence factors to successfully establish urinary tract infections. Hemolysin is a pore-forming toxin, and its expression correlates with the severity of UPEC infection. Two-component signaling systems (TCSs) are a major mechanism by which bacteria sense environmental cues and respond by initiating adaptive responses. Here, we began this study by characterizing a novel TCS (C3564/C3565, herein renamed orhK/orhR for oxidative resistance and hemolysis kinase/regulator) that is encoded on a UPEC pathogenicity island, using bioinformatic and biochemical approaches. A prevalence analysis indicates that orhK/orhR is highly associated with the UPEC pathotype, and it rarely occurs in other E. coli pathotypes tested. We then demonstrated that OrhK/OrhR directly activates the expression of a putative methionine sulfoxide reductase system (C3566/C3567) and hemolysin (HlyA) in response to host-derived hydrogen peroxide (H2O2) exposure. OrhK/OrhR increases UPEC resistance to H2O2 in vitro and survival in macrophages in cell culture via C3566/C3567. Additionally, OrhK/OrhR mediates hemolysin-induced renal epithelial cell and macrophage death via a pyroptosis pathway. Reducing intracellular H2O2 production by a chemical inhibitor impaired OrhK/OrhR-mediated activation of c3566-c3567 and hlyA. We also uncovered that UPEC links the two key virulence traits by cotranscribing the c3566-c3567 and hlyCABD operons. Taken together, our data suggest a paradigm in which a signal transduction system coordinates both bacterial pathogen defensive and offensive traits in the presence of host-derived signals; and this exquisite mechanism likely contributes to hemolysin-induced severe pathological outcomes.

Author summary Uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infections, and approximately half of UPEC isolates produce a pore-forming toxin, hemolysin. Clinically, hemolysin carriage is associated with severe pathology and symptoms during UPEC infections. However, overexpression of hemolysin can be detrimental to UPEC colonization. Therefore, fine-tuning of hemolysin expression in response to in vivo-relevant signals is critical for optimal UPEC fitness in the urinary tract. In this study, we describe a virulence strategy employed by UPEC, i.e., the bacteria use a two-component signaling (TCS) system to coordinate oxidative stress resistance and hemolysin-mediated pyroptosis of host cells in response to host-derived oxidative signals. The TCS achieves this coordination by cotranscribing genes encoding the oxidative stress resistance and the hemolysin. As a result, UPEC is able to link defense to offense, and this exquisite virulence mechanism likely contributes to UPEC fitness in vivo and hemolysin-induced severe pathological outcomes.

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