Shiga toxin suppresses noncanonical inflammasome responses to cytosolic LPS.
Shiga toxin suppresses noncanonical inflammasome responses to cytosolic LPS.
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滋贺毒素抑制对胞质LPS的非典型炎性体反应。
DOI：
10.1126/sciimmunol.abc0217
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发表时间：
2020-11-27
影响因子：
24.8
通讯作者：
Vanaja SK
中科院分区：
文献类型：
--
作者：
Havira MS;Ta A;Kumari P;Wang C;Russo AJ;Ruan J;Rathinam VA;Vanaja SK
炎症性caspase依赖的胞浆内毒素传感是宿主抵御细菌的关键武器。病原体如何克服这一途径来建立感染在很大程度上是未知的。肠出血性大肠埃希菌(EHEC)是引起出血性结肠炎和溶血性尿毒症综合征的重要人类病原体。我们发现，EHEC的一种噬菌体编码的毒力因子志贺毒素(STX)可以抑制caspase-11介导的胞浆内毒素传感通路的激活。STX对于抑制胞浆内毒素诱导的炎症性下垂和IL-1反应是必要和充分的。STX的催化活性是抑制炎症体反应所必需的。炎症体对胞浆内毒素反应的STX损伤发生在Gasdermin D激活水平。值得注意的是，STX可抑制脂多糖攻击时的炎症体反应以及体内的细菌感染。总体而言，这项研究将一种以前未描述的炎症体颠覆功能分配给一种众所周知的细菌毒素STX，并揭示了一种新的基于噬菌体蛋白的病原体对细胞质免疫监视的阻断。志贺毒素是一种噬菌体编码的细菌毒力因子，它抑制caspase-11介导的炎症体反应。
Inflammatory caspase-dependent cytosolic LPS sensing is a critical arm of host defense against bacteria. How pathogens overcome this pathway to establish infections is largely unknown. Enterohemorrhagic Escherichia coli (EHEC) is a clinically significant human pathogen causing hemorrhagic colitis and hemolytic uremic syndrome. We found that a bacteriophage-encoded virulence factor of EHEC, Shiga toxin (Stx), suppresses caspase-11-mediated activation of the cytosolic LPS sensing pathway. Stx was essential and sufficient to inhibit pyroptosis and IL-1 responses elicited specifically by cytosolic LPS. The catalytic activity of Stx was necessary for suppression of inflammasome responses. Stx impairment of inflammasome responses to cytosolic LPS occurs at the level of gasdermin D activation. Notably, Stx suppresses inflammasome responses during LPS challenge as well as bacterial infection in vivo. Overall, this study assigns a previously undescribed inflammasome-subversive function to a well-known bacterial toxin, Stx, and reveals a new phage protein-based pathogen blockade of cytosolic immune surveillance. Shiga toxin, a phage-encoded bacterial virulence factor, inhibits caspase-11-mediated inflammasome responses.
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