组织因子途径抑制物（TFPI）是来自高毒力2型艰难梭菌的TcdB的结肠隐窝受体。

TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile.

作者信息

Luo Jianhua, Yang Qi, Zhang Xiaofeng, Zhang Yuanyuan, Wan Li, Zhan Xiechao, Zhou Yao, He Liuqing, Li Danyang, Jin Dazhi, Zhen Ying, Huang Jing, Li Yanyan, Tao Liang

机构信息

Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China.

Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China.

出版信息

Cell. 2022 Mar 17;185(6):980-994.e15. doi: 10.1016/j.cell.2022.02.010.

DOI:10.1016/j.cell.2022.02.010

PMID:35303428

Abstract

The emergence of hypervirulent clade 2 Clostridioides difficile is associated with severe symptoms and accounts for >20% of global infections. TcdB is a dominant virulence factor of C. difficile, and clade 2 strains exclusively express two TcdB variants (TcdB2 and TcdB4) that use unknown receptors distinct from the classic TcdB. Here, we performed CRISPR/Cas9 screens for TcdB4 and identified tissue factor pathway inhibitor (TFPI) as its receptor. Using cryo-EM, we determined a complex structure of the full-length TcdB4 with TFPI, defining a common receptor-binding region for TcdB. Residue variations within this region divide major TcdB variants into 2 classes: one recognizes Frizzled (FZD), and the other recognizes TFPI. TFPI is highly expressed in the intestinal glands, and recombinant TFPI protects the colonic epithelium from TcdB2/4. These findings establish TFPI as a colonic crypt receptor for TcdB from clade 2 C. difficile and reveal new mechanisms for CDI pathogenesis.

摘要

高毒力2型艰难梭菌的出现与严重症状相关，占全球感染病例的20%以上。TcdB是艰难梭菌的主要毒力因子，2型菌株仅表达两种TcdB变体（TcdB2和TcdB4），它们使用不同于经典TcdB的未知受体。在此，我们对TcdB4进行了CRISPR/Cas9筛选，并确定组织因子途径抑制剂（TFPI）为其受体。利用冷冻电镜，我们确定了全长TcdB4与TFPI的复合物结构，定义了TcdB的共同受体结合区域。该区域内的残基变异将主要的TcdB变体分为两类：一类识别卷曲蛋白（FZD），另一类识别TFPI。TFPI在肠腺中高表达，重组TFPI可保护结肠上皮免受TcdB2/4的侵害。这些发现确定TFPI为2型艰难梭菌TcdB的结肠隐窝受体，并揭示了艰难梭菌感染发病机制的新机制。