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

Autor: Tian S; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA. Songhai.tian@childrens.harvard.edu.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. Songhai.tian@childrens.harvard.edu., Xiong X; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA., Zeng J; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA.; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China., Wang S; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA.; Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China., Tremblay BJ; Department of Biology, Cheriton School of Computer Science, and Waterloo Centre for Microbial Research, University of Waterloo, Waterloo, ON, N2L 3G1, Canada., Chen P; Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA., Chen B; Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA., Liu M; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA., Chen P; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA., Sheng K; Wyss Institute for Bioinspired Engineering, Harvard University, Boston, MA, 02115, USA., Zeve D; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA., Qi W; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA., Breault DT; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.; Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, MA, 02138, USA., Rodríguez C; Faculty of Microbiology & CIET, University of Costa Rica, San José, Costa Rica., Gerhard R; Institute of Toxicology, Hannover Medical School, 30625, Hannover, Germany., Jin R; Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, CA, 92697, USA., Doxey AC; Department of Biology, Cheriton School of Computer Science, and Waterloo Centre for Microbial Research, University of Waterloo, Waterloo, ON, N2L 3G1, Canada. acdoxey@uwaterloo.ca., Dong M; Department of Urology, Boston Children's Hospital, Boston, MA, 02115, USA. min.dong@childrens.harvard.edu.; Department of Microbiology and Department of Surgery, Harvard Medical School, Boston, MA, 02115, USA. min.dong@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Nov 09; Vol. 13 (1), pp. 6786. Date of Electronic Publication: 2022 Nov 09.
DOI: 10.1038/s41467-022-33964-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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