TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile
TFPI is a colonic crypt receptor for TcdB from hypervirulent clade 2 C. difficile
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DOI：
10.1016/j.cell.2022.02.010
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发表时间：
2022-03-17
期刊：
影响因子：
64.5
通讯作者：
Tao, Liang
中科院分区：
文献类型：
--
作者：
Luo, Jianhua;Yang, Qi;Tao, Liang
超强毒力艰难梭状芽胞杆菌2分支的出现与严重的症状有关，占全球感染的20%。TcdB是艰难梭菌的主要毒力因子，而分支2菌株只表达两个TcdB变异体(TcdB2和TcdB4)，它们使用与经典TcdB不同的未知受体。在这里，我们对TcdB4进行了CRISPR/Cas9筛查，并确定组织因子途径抑制物(TFPI)为其受体。利用冷冻-EM技术，我们确定了全长TcdB4与TFPI的复杂结构，定义了TcdB的共同受体结合区。该区域内的残基变异将主要的TcdB变异分为两类：一类识别Frizzled(FZD)，另一类识别TFPI。TFPI在肠腺中高度表达，重组TFPI保护结肠上皮细胞免受TcdB2/4的侵袭。这些发现证实了TFPI是艰难梭菌TcdB的结肠隐窝受体，并揭示了CDI发病的新机制。
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.