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 Yla-Herttuala, Alan C. Moss, Daniel Paredes-Sabja, Charalabos PothoulakisYatrik M. Shah, Jianping Wang, Xinhua Chen

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

11 Citas (Scopus)

Resumen

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.

Idioma originalInglés
Páginas (desde-hasta)269-279
Número de páginas11
PublicaciónNature Microbiology
Volumen4
N.º2
DOI
EstadoEn prensa - 1 ene 2018

Áreas temáticas de ASJC Scopus

  • Microbiología
  • Inmunología
  • Microbiología y biotecnología aplicadas
  • Genética
  • Microbiología (médica)
  • Biología celular

Huella Profundice en los temas de investigación de 'Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis'. En conjunto forman una huella única.

Citar esto