Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2021 Jun 18;12(1):3748. doi: 10.1038/s41467-021-23878-3.
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.
艰难梭菌是抗生素相关性胃肠道感染的主要原因。两种艰难梭菌外毒素（TcdA 和 TcdB）是与这些感染相关的主要毒力因子，而软骨素硫酸蛋白聚糖 4（CSPG4）是 TcdB 的潜在受体，但它的病理生理学相关性和控制识别的分子细节仍不清楚。在这里，我们确定了 TcdB-CSPG4 复合物的低温电子显微镜结构，揭示了一个独特的结合位点，其空间上由 TcdB 中的多个不连续区域组成。选择性破坏 CSPG4 结合的突变会降低 TcdB 在小鼠中的毒性，而 CSPG4 敲除小鼠在艰难梭菌感染期间结肠组织的损伤减少。我们进一步表明，贝洛妥珠单抗是唯一获得 FDA 批准的抗 TcdB 抗体，通过变构机制阻断 CSPG4 结合，但由于其表位的序列变异，它对来自流行高毒力株的许多 TcdB 变体的中和效力较低。相比之下，CSPG4 模拟诱饵可以中和主要的 TcdB 变体，这表明开发针对 TcdB 的广谱治疗策略的可能性。
Zotero 插件
