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

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 () and Rongsheng Jin ()
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Peng Chen: University of California
Ji Zeng: Harvard Medical School
Zheng Liu: University of California
Hatim Thaker: Harvard Medical School
Siyu Wang: Harvard Medical School
Songhai Tian: Harvard Medical School
Jie Zhang: Harvard Medical School
Liang Tao: Westlake University
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
Rongsheng Jin: University of California

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23878-3

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