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 Pothoulakis & 3 others Yatrik M. Shah, Jianping Wang, Xinhua Cheng

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Huang, Jun ; Kelly, Ciarán P. ; Bakirtzi, Kyriaki ; Villafuerte Gálvez, Javier A. ; Lyras, Dena ; Mileto, Steven J. ; Larcombe, Sarah ; Xu, Hua ; Yang, Xiaotong ; Shields, Kelsey S. ; Zhu, Weishu ; Zhang, Yi ; Goldsmith, Jeffrey D. ; Patel, Ishan J. ; Hansen, Joshua ; Huang, Meijin ; Ylä-Herttuala, Seppo ; Moss, Alan C. ; Paredes-Sabja, Daniel ; Pothoulakis, Charalabos ; Shah, Yatrik M. ; Wang, Jianping ; Cheng, Xinhua. / Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis. In: Nature Microbiology. 2019 ; Vol. 4.
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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 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.",
keywords = "bacterial pathogenesis, bacterial toxins, clostridium difficile, gastrointestinal diseases, infections",
author = "Jun Huang and Kelly, {Ciar{\'a}n P.} and Kyriaki Bakirtzi and {Villafuerte G{\'a}lvez}, {Javier A.} and Dena Lyras and Mileto, {Steven J.} and Sarah Larcombe and Hua Xu and Xiaotong Yang and Shields, {Kelsey S.} and Weishu Zhu and Yi Zhang and Goldsmith, {Jeffrey D.} and Patel, {Ishan J.} and Joshua Hansen and Meijin Huang and Seppo Yl{\"a}-Herttuala and Moss, {Alan C.} and Daniel Paredes-Sabja and Charalabos Pothoulakis and Shah, {Yatrik M.} and Jianping Wang and Xinhua Cheng",
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Huang, J, Kelly, CP, Bakirtzi, K, Villafuerte Gálvez, JA, Lyras, D, Mileto, SJ, Larcombe, S, Xu, H, Yang, X, Shields, KS, Zhu, W, Zhang, Y, Goldsmith, JD, Patel, IJ, Hansen, J, Huang, M, Ylä-Herttuala, S, Moss, AC, Paredes-Sabja, D, Pothoulakis, C, Shah, YM, Wang, J & Cheng, X 2019, 'Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis' Nature Microbiology, vol. 4. https://doi.org/10.1038/s41564-018-0300-x

Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis. / Huang, Jun; Kelly, Ciarán P.; Bakirtzi, Kyriaki; Villafuerte Gálvez, Javier A.; Lyras, Dena; Mileto, Steven J.; Larcombe, Sarah; Xu, Hua; Yang, Xiaotong; Shields, Kelsey S.; Zhu, Weishu; Zhang, Yi; Goldsmith, Jeffrey D. ; Patel, Ishan J.; Hansen, Joshua; Huang, Meijin; Ylä-Herttuala, Seppo; Moss, Alan C.; Paredes-Sabja, Daniel; Pothoulakis, Charalabos; Shah, Yatrik M.; Wang, Jianping; Cheng, Xinhua.

In: Nature Microbiology, Vol. 4, 02.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis

AU - Huang, Jun

AU - Kelly, Ciarán P.

AU - Bakirtzi, Kyriaki

AU - Villafuerte Gálvez, Javier A.

AU - Lyras, Dena

AU - Mileto, Steven J.

AU - Larcombe, Sarah

AU - Xu, Hua

AU - Yang, Xiaotong

AU - Shields, Kelsey S.

AU - Zhu, Weishu

AU - Zhang, Yi

AU - Goldsmith, Jeffrey D.

AU - Patel, Ishan J.

AU - Hansen, Joshua

AU - Huang, Meijin

AU - Ylä-Herttuala, Seppo

AU - Moss, Alan C.

AU - Paredes-Sabja, Daniel

AU - Pothoulakis, Charalabos

AU - Shah, Yatrik M.

AU - Wang, Jianping

AU - Cheng, Xinhua

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

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KW - bacterial toxins

KW - clostridium difficile

KW - gastrointestinal diseases

KW - infections

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JF - Nature Microbiology

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