Journal Article

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

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

2019

Overview

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. Clostridium difficile toxins TcdA and TcdB enhance pathogenesis by inducing vascular endothelial growth factor A (VEGF-A) production and promoting colonic vascular permeability.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/41/1319 / 631/326/41/2531 / 64/60 / 692/4020/1503 / 692/420/254 / 692/699/255/1911 / Animals / Bacterial Toxins - genetics / Bacterial Toxins - metabolism / Biomedical and Life Sciences / Capillary Permeability / Clostridium difficile / Clostridium difficile - chemistry / Clostridium difficile - pathogenicity / Clostridium Infections - metabolism / Clostridium Infections - pathology / Colon - metabolism / Colon - pathology / Endothelial cells / Enterotoxins - genetics / Enterotoxins - metabolism / Epithelium - metabolism / Epithelium - pathology / Exotoxins / Humans / Hypoxia-Inducible Factor 1 - metabolism / Hypoxia-inducible factors / Infectious Diseases / Inflammation / Intestine / Life Sciences / Medical Microbiology / Mice / Microbiology / Microvasculature / Mucosa / Neovascularization, Pathologic / Parasitology / Pathogenesis / Pathogens / Permeability / Signal Transduction / Survival Analysis / Toxin A / Toxin B / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - antagonists & inhibitors / Vascular Endothelial Growth Factor A - blood / Vascular Endothelial Growth Factor A - metabolism / Virology / Virulence factors / Virulence Factors - genetics / Virulence Factors - metabolism