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Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection

Author

Listed:
  • Peng Chen

    (University of California)

  • Ji Zeng

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Zheng Liu

    (University of California)

  • Hatim Thaker

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Siyu Wang

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School
    China-Japan Union Hospital of Jilin University)

  • Songhai Tian

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Jie Zhang

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Liang Tao

    (Westlake University
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Craig B. Gutierrez

    (University of California)

  • Li Xing

    (University of California)

  • Ralf Gerhard

    (Institute of Toxicology, Hannover Medical School)

  • Lan Huang

    (University of California)

  • Min Dong

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Rongsheng Jin

    (University of California)

Abstract

C. difficile is a major cause of antibiotic-associated gastrointestinal infections. Two C. difficile exotoxins (TcdA and TcdB) are major virulence factors associated with these infections, and chondroitin sulfate proteoglycan 4 (CSPG4) is a potential receptor for TcdB, but its pathophysiological relevance and the molecular details that govern recognition remain unknown. Here, we determine the cryo-EM structure of a TcdB–CSPG4 complex, revealing a unique binding site spatially composed of multiple discontinuous regions across TcdB. Mutations that selectively disrupt CSPG4 binding reduce TcdB toxicity in mice, while CSPG4-knockout mice show reduced damage to colonic tissues during C. difficile infections. We further show that bezlotoxumab, the only FDA approved anti-TcdB antibody, blocks CSPG4 binding via an allosteric mechanism, but it displays low neutralizing potency on many TcdB variants from epidemic hypervirulent strains due to sequence variations in its epitopes. In contrast, a CSPG4-mimicking decoy neutralizes major TcdB variants, suggesting a strategy to develop broad-spectrum therapeutics against TcdB.

Suggested Citation

  • Peng Chen & Ji Zeng & Zheng Liu & Hatim Thaker & Siyu Wang & Songhai Tian & Jie Zhang & Liang Tao & Craig B. Gutierrez & Li Xing & Ralf Gerhard & Lan Huang & Min Dong & Rongsheng Jin, 2021. "Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23878-3
    DOI: 10.1038/s41467-021-23878-3
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    Cited by:

    1. Ruoyu Zhou & Liuqing He & Jiahao Zhang & Xiaofeng Zhang & Yanyan Li & Xiechao Zhan & Liang Tao, 2024. "Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. 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 & Cé, 2022. "Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Xingxing Li & Liuqing He & Jianhua Luo & Yangling Zheng & Yao Zhou & Danyang Li & Yuanyuan Zhang & Zhenrui Pan & Yanyan Li & Liang Tao, 2022. "Paeniclostridium sordellii hemorrhagic toxin targets TMPRSS2 to induce colonic epithelial lesions," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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