Department of Immunology, UConn Health School of Medicine, 263 Farmington Ave., Farmington, CT 06030, USA.
Sci Immunol. 2020 Nov 27;5(53). doi: 10.1126/sciimmunol.abc0217.
Inflammatory caspase-dependent cytosolic lipopolysaccharide (LPS) sensing is a critical arm of host defense against bacteria. How pathogens overcome this pathway to establish infections is largely unknown. Enterohemorrhagic (EHEC) is a clinically important 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 interleukin-1 (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. Stx also suppresses inflammasome responses in vivo after LPS challenge and bacterial infection. 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.
炎症性半胱天冬酶依赖性细胞溶质脂多糖 (LPS) 感应是宿主防御细菌的重要手段。病原体如何克服这条途径来建立感染在很大程度上是未知的。肠出血性 (EHEC) 是一种临床重要的人类病原体，可引起出血性结肠炎和溶血性尿毒症综合征。我们发现，EHEC 的噬菌体编码的毒力因子志贺毒素 (Stx) 抑制了细胞溶质 LPS 感应途径中介导的半胱天冬酶-11 的激活。Stx 是抑制由细胞溶质 LPS 特异性引发的细胞焦亡和白细胞介素-1 (IL-1) 反应所必需和充分的。Stx 的催化活性对于抑制炎症小体反应是必要的。Stx 在 Gasdermin D 激活水平上损害了对细胞溶质 LPS 的炎症小体反应。Stx 还在 LPS 挑战和细菌感染后抑制体内的炎症小体反应。总的来说，这项研究赋予了一种众所周知的细菌毒素——Stx 以前未描述的炎症小体抑制功能，并揭示了一种新的基于噬菌体蛋白的病原体对细胞溶质免疫监视的阻断作用。
