Journal
CELL
Volume 185, Issue 6, Pages 980-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2022.02.010
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [31970129, 31800128, 32171205]
- Zhejiang Provincial Natural Science Foundation of China [LR20C010001, LR20C050001]
- Westlake Education Foundation
- Westlake Laboratory of Life Sciences and Biomedicine
Ask authors/readers for more resources
The study identified tissue factor pathway inhibitor (TFPI) as the receptor for TcdB4, a dominant virulence factor of hypervirulent clade 2 Clostridioides difficile. TFPI is highly expressed in the intestinal glands and protects the colonic epithelium from TcdB2/4. These findings reveal new mechanisms for CDI pathogenesis.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available