ArcA positively regulates the expression of virulence genes and contributes to virulence of porcine Shiga toxin-producing enterotoxigenic Escherichia coli.
ArcA positively regulates the expression of virulence genes and contributes to virulence of porcine Shiga toxin-producing enterotoxigenic Escherichia coli.
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DOI：
10.1128/spectrum.01525-23
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发表时间：
2023-12-12
影响因子：
3.7
通讯作者：
Li, Ganwu
中科院分区：
文献类型：
--
作者：
Jiang, Fengwei;Yang, Yan;Mao, Zhao;Cai, Wentong;Li, Ganwu
关键词：
产肠毒素大肠杆菌 (ETEC) 会导致人类和动物严重腹泻。这些细菌编码两大类毒力因子：促进小肠定植的粘附素和诱导液体分泌并因此引起腹泻的肠毒素。氧和氧化还原传感器是多种细菌病原体毒力表达的调节因子。在这项研究中，我们发现微氧条件增强了猪志贺毒素 ETEC (STEC/ETEC) 菌株中毒力因子的表达。然后我们研究了有氧呼吸控制调节剂 ArcA 在 STEC/ETEC 致病性和毒力调节中的作用。在小鼠模型中，删除 arcA 引起的病理不太严重，与野生型 (WT) 相比，arcA 突变体表现出较低的定植水平和明显的小鼠体重增加。在细胞培养模型中，arcA 的缺乏会降低 STEC/ETEC 对猪肠上皮细胞的粘附。此外，在微氧条件和体内条件下，ArcA 正向调节几个关键毒力因子的表达，包括 F18 菌毛（fed）、不耐热（eltA）和热稳定（estB）毒素、志贺毒素 2e（stx2e）和溶血素（hlyC）。然后我们发现 ArcA 通过与全局阻遏蛋白 H-NS（组蛋白样核结构）竞争，正向调节 eltA、estB 和 hlyC 的表达。从机制上讲，我们发现 ArcA 蛋白直接与靶基因的启动子结合，取代启动子上的 H-NS 沉默并抵消 H-NS 的抑制。总的来说，我们的数据确定了 ArcA 在猪 STEC/ETEC 致病性和毒力表达中的关键作用。产肠毒素大肠杆菌 (ETEC) 会导致人类和动物严重腹泻，在全世界范围内导致死亡和巨大的经济损失。因此，阐明 ETEC 的致病机制将为开发预防或治疗 ETEC 引起的腹泻疾病的药物提供有力的数据。在这里，我们报道，在微氧条件下和体内，ArcA 通过正向调节几个关键毒力因子的表达，包括 F18 菌毛、热不稳定和热稳定毒素、志贺毒素 2e 和溶血素，在 ETEC 的致病性和毒力调节中发挥重要作用。此外，我们发现ArcA对多个毒力基因的正向调节需要全局阻遏物H-NS（组蛋白样核结构），这意味着ArcA可能通过拮抗H-NS来发挥积极作用。总的来说，我们的数据确定了 ArcA 在猪 ETEC 和从人类感染中分离出的 ETEC 菌株的致病性中发挥着关键作用。此外，我们的工作揭示了与 ETEC 毒力因子的氧控制相关的另一层调节。
Enterotoxigenic Escherichia coli (ETEC) cause severe diarrhea in humans and animals. These bacteria encode two major classes of virulence factors, adhesins that promote colonization of the small intestine and enterotoxins that induce fluid secretion and thus diarrhea. Oxygen and redox sensors are regulators of virulence expression in multiple bacterial pathogens. In this study, we show that microaerobic conditions enhance the expression of virulence factors in a porcine Shiga toxin-producing ETEC (STEC/ETEC) strain. We then investigated the role of the aerobic respiration control regulator ArcA in the pathogenicity and virulence regulation in STEC/ETEC. In a mouse model, deletion of arcA caused less severe pathology, and the arcA mutant displayed lower levels of colonization and obvious weight gain of the mice compared to the wild type (WT). In a cell culture model, a lack of arcA reduced the adherence of STEC/ETEC to porcine intestinal epithelial cells. Furthermore, ArcA positively regulated the expression of several key virulence factors, including F18 fimbriae (fed), heat-labile (eltA) and heat-stable (estB) toxins, Shiga toxin 2e (stx2e), and hemolysin (hlyC), under microaerobic conditions and in vivo conditions. We then found that ArcA positively regulated the expression of eltA, estB, and hlyC by competing with a global repressor H-NS (histone-like nucleoid structuring). Mechanistically, we show that ArcA protein directly binds to the promoters of target genes, displaces H-NS silencing from the promoter and counteracts H-NS’s repression. Collectively, our data established a key role for ArcA in the pathogenicity and virulence expression of porcine STEC/ETEC. Enterotoxigenic Escherichia coli (ETEC) cause severe diarrhea in humans and animals, leading to death and huge economic loss worldwide. Thus, elucidation of ETEC’s pathogenic mechanisms will provide powerful data for the discovery of drugs serving as prevention or therapeutics against ETEC-caused diarrheal diseases. Here, we report that ArcA plays an essential role in the pathogenicity and virulence regulation in ETEC by positively regulating the expression of several key virulence factors including F18 fimbriae, heat-labile and heat-stable toxins, Shiga toxin 2e, and hemolysin, under microaerobic conditions and in vivo. Moreover, we found that positive regulation of several virulence genes by ArcA requires a global repressor H-NS (histone-like nucleoid structuring), implying that ArcA may exert positive effects by antagonizing H-NS. Collectively, our data established a key role for ArcA in the pathogenicity of porcine ETEC and ETEC strains isolated from human infections. Moreover, our work reveals another layer of regulation in relation to oxygen control of virulence factors in ETEC.
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影响因子：
3.2
作者：
Baldo V;Salogni C;Giovannini S;D'Incau M;Boniotti MB;Birbes L;Pitozzi A;Formenti N;Grassi A;Pasquali P;Alborali GL
通讯作者：
Alborali GL
影响因子：
4.6
作者：
通讯作者：
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影响因子：
3.2
作者：
Bekker, Martijn;Alexeeva, Svetlana;Hellingwerf, Klaas
通讯作者：
Hellingwerf, Klaas
影响因子：
34.3
作者：
Anderson, John D.;Bagamian, Karoun H.;Rheingans, Richard
通讯作者：
Rheingans, Richard
影响因子：
2.8
作者：
Guth, BEC
通讯作者：
Guth, BEC