Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis
Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis
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DOI：
10.1038/s41564-018-0300-x
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发表时间：
2019-02-01
影响因子：
28.3
通讯作者：
Chen, Xinhua
中科院分区：
文献类型：
--
作者：
Huang, Jun;Kelly, Ciaran P.;Chen, Xinhua
艰难梭菌感染 (CDI) 由两种主要外毒素介导，即毒素 A (TcdA) 和毒素 B (TcdB)，它们会损害结肠上皮屏障并诱导炎症反应。 CDI 期间结肠血管屏障的功能研究相对较少。在这里，我们报告了 CDI 小鼠的结肠血管通透性增加和血管内皮生长因子 A (VEGF-A) 升高，这是在体内通过感染 TcdA 和/或 TcdB 产生 TcdB 的艰难梭菌菌株诱导的，但不是 TcdA(-) TcdB(-) 同基因突变体感染的。 TcdA 或 TcdB 还在人结肠粘膜活检中诱导 VEGF-A 的表达。缺氧诱导因子信号传导似乎介导结肠细胞中毒素诱导的 VEGF 产生，这可以进一步刺激人肠道微血管内皮细胞。 VEGF-A 的中和及其信号通路的抑制均可减弱体内 CDI。与健康对照者相比，CDI 患者的血清 VEGF-A 显着升高，随后治疗后下降。我们的研究结果表明毒素诱导的 VEGF-A 和结肠血管通透性在 CDI 发病机制中的关键作用，也可能指出肠道血管屏障响应肠道病原体毒力因子的病理生理学意义。作为病原体靶向治疗的替代方案，这项研究可能为严重、难治性 CDI 提供新的宿主导向治疗方法。
Clostridium difficile infection (CDI) is mediated by two major exotoxins, toxin A (TcdA) and toxin B (TcdB), that damage the colonic epithelial barrier and induce inflammatory responses. The function of the colonic vascular barrier during CDI has been relatively understudied. Here we report increased colonic vascular permeability in CDI mice and elevated vascular endothelial growth factor A (VEGF-A), which was induced in vivo by infection with TcdA- and/or TcdB-producing C. difficile strains but not with a TcdA(-) TcdB(-) isogenic mutant. TcdA or TcdB also induced the expression of VEGF-A in human colonic mucosal biopsies. Hypoxia-inducible factor signalling appeared to mediate toxin-induced VEGF production in colonocytes, which can further stimulate human intestinal microvascular endothelial cells. Both neutralization of VEGF-A and inhibition of its signalling pathway attenuated CDI in vivo. Compared to healthy controls, CDI patients had significantly higher serum VEGF-A that subsequently decreased after treatment. Our findings indicate critical roles for toxin-induced VEGF-A and colonic vascular permeability in CDI pathogenesis and may also point to the pathophysiological significance of the gut vascular barrier in response to virulence factors of enteric pathogens. As an alternative to pathogen-targeted therapy, this study may enable new host-directed therapeutic approaches for severe, refractory CDI.