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

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dc.contributor.authorHuang, Jun
dc.contributor.authorKelly, Ciarán P.
dc.contributor.authorBakirtzi, Kyriaki
dc.contributor.authorVillafuerte Gálvez, Javier A.
dc.contributor.authorLyras, Dena
dc.contributor.authorMileto, Steven J.
dc.contributor.authorLarcombe, Sarah
dc.contributor.authorXu, Hua
dc.contributor.authorYang, Xiaotong
dc.contributor.authorShields, Kelsey S.
dc.contributor.authorZhu, Weishu
dc.contributor.authorZhang, Yi
dc.contributor.authorGoldsmith, Jeffrey D.
dc.contributor.authorPatel, Ishan J.
dc.contributor.authorHansen, Joshua
dc.contributor.authorHuang, Meijin
dc.contributor.authorYla-Herttuala, Seppo
dc.contributor.authorMoss, Alan C.
dc.contributor.authorParedes-Sabja, Daniel
dc.contributor.authorPothoulakis, Charalabos
dc.contributor.authorShah, Yatrik M.
dc.contributor.authorWang, Jianping
dc.contributor.authorChen, Xinhua
dc.date.accessioned2024-06-21T20:37:46Z
dc.date.available2024-06-21T20:37:46Z
dc.date.issued2019-02-01
dc.descriptionIndexación: Scopus.
dc.description.abstractClostridium 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.
dc.description.urihttps://www-nature-com.recursosbiblioteca.unab.cl/articles/s41564-018-0300-x
dc.identifier.citationNature Microbiology Volume 4, Issue 2, Pages 269 - 279 1 February 2019
dc.identifier.doi10.1038/s41564-018-0300-x
dc.identifier.issn2058-5276
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/57848
dc.language.isoen_US
dc.publisherNature Publishing Group
dc.rights.licenseATRIBUCIÓN 4.0 INTERNACIONAL
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/deed.es
dc.titleClostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis
dc.typeArtículo
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