Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants

Songhai Tian (), Xiaozhe Xiong, Ji Zeng, Siyu Wang, Benjamin Jean-Marie Tremblay, Peng Chen, Baohua Chen, Min Liu, Pengsheng Chen, Kuanwei Sheng, Daniel Zeve, Wanshu Qi, David T. Breault, César Rodríguez, Ralf Gerhard, Rongsheng Jin, Andrew C. Doxey () and Min Dong ()
Additional contact information
Songhai Tian: Boston Children’s Hospital
Xiaozhe Xiong: Boston Children’s Hospital
Ji Zeng: Boston Children’s Hospital
Siyu Wang: Boston Children’s Hospital
Benjamin Jean-Marie Tremblay: University of Waterloo
Peng Chen: University of California Irvine
Baohua Chen: University of California Irvine
Min Liu: Boston Children’s Hospital
Pengsheng Chen: Boston Children’s Hospital
Kuanwei Sheng: Harvard University
Daniel Zeve: Boston Children’s Hospital
Wanshu Qi: Boston Children’s Hospital
David T. Breault: Boston Children’s Hospital
César Rodríguez: University of Costa Rica
Ralf Gerhard: Hannover Medical School
Rongsheng Jin: University of California Irvine
Andrew C. Doxey: University of Waterloo
Min Dong: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Toxin B (TcdB) is a major exotoxin responsible for diseases associated with Clostridioides difficile infection. Its sequence variations among clinical isolates may contribute to the difficulty in developing effective therapeutics. Here, we investigate receptor-binding specificity of major TcdB subtypes (TcdB1 to TcdB12). We find that representative members of subtypes 2, 4, 7, 10, 11, and 12 do not recognize the established host receptor, frizzled proteins (FZDs). Using a genome-wide CRISPR-Cas9-mediated screen, we identify tissue factor pathway inhibitor (TFPI) as a host receptor for TcdB4. TFPI is recognized by a region in TcdB4 that is homologous to the FZD-binding site in TcdB1. Analysis of 206 TcdB variant sequences reveals a set of six residues within this receptor-binding site that defines a TFPI binding-associated haplotype (designated B4/B7) that is present in all TcdB4 members, a subset of TcdB7, and one member of TcdB2. Intragenic micro-recombination (IR) events have occurred around this receptor-binding region in TcdB7 and TcdB2 members, resulting in either TFPI- or FZD-binding capabilities. Introduction of B4/B7-haplotype residues into TcdB1 enables dual recognition of TFPI and FZDs. Finally, TcdB10 also recognizes TFPI, although it does not belong to the B4/B7 haplotype, and shows species selectivity: it recognizes TFPI of chicken and to a lesser degree mouse, but not human, dog, or cattle versions. These findings identify TFPI as a TcdB receptor and reveal IR-driven changes on receptor-specificity among TcdB variants.

Date: 2022
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DOI: 10.1038/s41467-022-33964-9

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