S-nitrosylation-mediated activation of a histidine kinase represses the type 3 secretion system and promotes virulence of an enteric pathogen.
S-nitrosylation-mediated activation of a histidine kinase represses the type 3 secretion system and promotes virulence of an enteric pathogen.
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DOI：
10.1038/s41467-020-19506-1
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发表时间：
2020-11-13
影响因子：
16.6
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Gu D;Zhang Y;Wang Q;Zhou X
副溶血性弧菌是导致海产品传播性腹泻病的主要原因。实验过度生产的3型分泌系统（T3 SS 1）在这种病原体导致肠道定植减少，这表明，T3 SS 1的镇压是需要最大的毒力。然而，T3 SS 1在体内被抑制的机制尚不清楚。在这里，我们表明，主机衍生的亚硝酸盐修改细菌组氨酸激酶的活性和介导的T3 SS 1抑制。更具体地说，亚硝酸盐通过半胱氨酸86上的S-亚硝基化激活组氨酸激酶传感器VbrK，这导致整个T3 SS 1操纵子通过抑制其正调节因子exsC而下调。用丝氨酸（VbrK C86 S突变体）替换半胱氨酸86导致感染的Caco-2细胞中炎性细胞因子的表达增加。在感染的幼兔模型中，与亲本菌株相比，VbrK C86 S突变体在感染的早期阶段诱导更强的炎症反应，并且在感染的后期阶段显示出降低的肠道定殖和毒力。我们的研究结果表明，病原体V. parahaemolyticus感知亚硝酸盐作为宿主来源的信号，并通过下调促炎因子（T3 SS 1），从而增强肠道定植和毒力。副溶血性弧菌引起海产品传播的腹泻病。在这里，作者表明病原体使用组氨酸激酶来感知宿主来源的亚硝酸盐并下调促炎性3型分泌系统，从而增强肠道定植和毒力。
Vibrio parahaemolyticus is the leading cause of seafood-borne diarrheal diseases. Experimental overproduction of a type 3 secretion system (T3SS1) in this pathogen leads to decreased intestinal colonization, which suggests that T3SS1 repression is required for maximal virulence. However, the mechanisms by which T3SS1 is repressed in vivo are unclear. Here, we show that host-derived nitrite modifies the activity of a bacterial histidine kinase and mediates T3SS1 repression. More specifically, nitrite activates histidine kinase sensor VbrK through S-nitrosylation on cysteine 86, which results in downregulation of the entire T3SS1 operon through repression of its positive regulator exsC. Replacement of cysteine 86 with a serine (VbrK C86S mutant) leads to increased expression of inflammatory cytokines in infected Caco-2 cells. In an infant rabbit model of infection, the VbrK C86S mutant induces a stronger inflammatory response at the early stage of infection, and displays reduced intestinal colonization and virulence at the later stage of infection, in comparison with the parent strain. Our results indicate that the pathogen V. parahaemolyticus perceives nitrite as a host-derived signal and responds by downregulating a proinflammatory factor (T3SS1), thus enhancing intestinal colonization and virulence. Vibrio parahaemolyticus causes seafood-borne diarrheal diseases. Here, the authors show that the pathogen uses a histidine kinase to sense host-derived nitrite and downregulate a proinflammatory type 3 secretion system, thus enhancing intestinal colonization and virulence.
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