The Bacillus cereus toxin alveolysin disrupts the intestinal epithelial barrier by inducing microtubule disorganization through CFAP100
The Bacillus cereus toxin alveolysin disrupts the intestinal epithelial barrier by inducing microtubule disorganization through CFAP100
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DOI：
10.1126/scisignal.ade8111
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发表时间：
2023-05-16
影响因子：
7.3
通讯作者：
Zhou，Jun
中科院分区：
文献类型：
--
作者：
Sun，Shuang;Xu，Zhaoyang;Zhou，Jun
蜡样芽孢杆菌是一种革兰氏阳性细菌，主要引起自限性呕吐或腹泻疾病，但也可引起皮肤感染和菌血症。症状 B.脑水肿取决于针对胃和肠上皮细胞的各种毒素的产生。通过对人类粪便样本中损害小鼠肠道屏障功能的细菌分离物进行筛选，我们鉴定出了 B.蜡状菌破坏了肠上皮的紧密和粘附连接。这种活性是由成孔外毒素肺泡溶血素介导的，它增加了肠上皮细胞中膜锚定蛋白 CD59 以及纤毛和鞭毛相关蛋白 100 (CFAP100) 的产生。在体外，CFAP100与微管相互作用并促进微管聚合。 CFAP100 过度表达可稳定肠上皮细胞中的微管，导致微管网络紊乱以及紧密连接和粘附连接的扰动。肺泡溶素对细胞连接的破坏取决于 CFAP100 的增加，而 CFAP100 的增加又取决于 CD59 和 PI3K-AKT 信号传导的激活。这些发现表明，除了形成膜孔外，B.蜡样肺溶血素可以通过破坏上皮细胞连接来透化肠上皮，其方式与肠道症状一致，并可能使细菌逸出肠道并引起全身感染。我们的结果表明以肺泡溶血素或 CFAP100 为目标来预防 B.蜡状菌相关肠道疾病和全身感染。
Bacillus cereusis a Gram-positive bacterium that mainly causes self-limiting emetic or diarrheal illness but can also cause skin infections and bacteremia. Symptoms ofB. cereusingestion depend on the production of various toxins that target the gastric and intestinal epithelia. From a screen of bacterial isolates from human stool samples that compromised intestinal barrier function in mice, we identified a strain ofB. cereusthat disrupted tight and adherens junctions in the intestinal epithelium. This activity was mediated by the pore-forming exotoxin alveolysin, which increased the production of the membrane-anchored protein CD59 and of cilia- and flagella-associated protein 100 (CFAP100) in intestinal epithelial cells. In vitro, CFAP100 interacted with microtubules and promoted microtubule polymerization. CFAP100 overexpression stabilized microtubules in intestinal epithelial cells, leading to disorganization of the microtubule network and perturbation of tight and adherens junctions. The disruption of cell junctions by alveolysin depended on the increase in CFAP100, which in turn depended on CD59 and the activation of PI3K-AKT signaling. These findings demonstrate that, in addition to forming membrane pores,B. cereusalveolysin can permeabilize the intestinal epithelium by disrupting epithelial cell junctions in a manner that is consistent with intestinal symptoms and may allow the bacteria to escape the intestine and cause systemic infections. Our results suggest the potential value of targeting alveolysin or CFAP100 to preventB. cereus–associated intestinal diseases and systemic infections.