TheBacillus cereustoxin alveolysin disrupts the intestinal epithelial barrier by inducing microtubule disorganization through CFAP100

• DOI: 10.1126/scisignal.ade8111
• Publication Date: 2023-05-16T17:58:51Z
• Authors: Shuang Sun; Zhaoyang Xu; Haijie Hu; Manxi Zheng; Liang Zhang; Wei Xie; Lei Sun; Peiwei Liu; Tianliang Li; Liangran Zhang; Min Chen; Xueliang Zhu; Min Liu; Yunfan Yang; Jun Zhou
• Keywords: Mice; Phosphatidylinositol 3-Kinases; 0303 health sciences; 03 medical and health sciences; Bacillus cereus; Flagella; Humans; Animals; Exotoxins; Cilia; Intestinal Mucosa

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.