Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis

Jun Huang, Ciarán P. Kelly, Kyriaki Bakirtzi, Javier A. Villafuerte Gálvez, Dena Lyras, Steven J. Mileto, Sarah Larcombe, Hua Xu, Xiaotong Yang, Kelsey S. Shields, Weishu Zhu, Yi Zhang, Jeffrey D. Goldsmith, Ishan J. Patel, Joshua Hansen, Meijin Huang, Seppo Ylä-Herttuala, Alan C. Moss, Daniel Paredes-Sabja, Charalabos PothoulakisYatrik M. Shah, Jianping Wang, Xinhua Cheng

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

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 TcdATcdB 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.

Original languageEnglish
Number of pages11
JournalNature Microbiology
Volume4
DOIs
Publication statusPublished - Feb 2019

Keywords

  • bacterial pathogenesis
  • bacterial toxins
  • clostridium difficile
  • gastrointestinal diseases
  • infections

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