Frizzled proteins are colonic epithelial receptors for C. difficile toxin B

Article

关键词: UDP-GLUCOSE DEFICIENCY;    CLOSTRIDIUM-DIFFICILE;    STEM-CELLS;    IN-VITRO;    INFECTION;    MODEL;    IDENTIFICATION;    TRANSLOCATION;    EXPRESSION;    VIRULENCE;   

DOI  :  10.1038/nature19799

来源: SCIE

【 摘 要 】

Clostridium difficile toxin B (TcdB) is a critical virulence factor that causes diseases associated with C. difficile infection. Here we carried out CRISPR-Cas9-mediated genome-wide screens and identified the members of the Wnt receptor frizzled family (FZDs) as TcdB receptors. TcdB binds to the conserved Wnt-binding site known as the cysteine-rich domain (CRD), with the highest affinity towards FZD1, 2 and 7. TcdB competes with Wnt for binding to FZDs, and its binding blocks Wnt signalling. FZD1/2/7 triple-knockout cells are highly resistant to TcdB, and recombinant FZD2-CRD prevented TcdB binding to the colonic epithelium. Colonic organoids cultured from FZD7-knockout mice, combined with knockdown of FZD1 and 2, showed increased resistance to TcdB. The colonic epithelium in FZD7-knockout mice was less susceptible to TcdB-induced tissue damage in vivo. These findings establish FZDs as physiologically relevant receptors for TcdB in the colonic epithelium.

【 授权许可】

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