PUBLICATION

Extra-Intestinal Effects of C.difficile Toxin A and B: An In Vivo Study Using the Zebrafish Embryo Model

Authors
Tonon, F., Di Bella, S., Grassi, G., Luzzati, R., Ascenzi, P., di Masi, A., Zennaro, C.
ID
ZDB-PUB-201208-18
Date
2020
Source
Cells   9(12): (Journal)
Registered Authors
Keywords
C. difficile infection, toxins, zebrafish
MeSH Terms
  • Disease Models, Animal
  • Cells, Cultured
  • Zebrafish/metabolism
  • Zebrafish/microbiology*
  • Bacterial Toxins/toxicity*
  • Natriuretic Peptide, Brain/metabolism
  • Caco-2 Cells
  • Human Umbilical Vein Endothelial Cells
  • Animals
  • Inflammation/chemically induced
  • Inflammation/metabolism
  • Clostridioides difficile/metabolism*
  • Humans
  • Cytokines/metabolism
  • Neutrophils/drug effects
  • Neutrophils/metabolism
  • Cell Line, Tumor
  • Clostridium Infections/complications*
  • Clostridium Infections/metabolism
  • Enterotoxins/toxicity
  • Intestines/drug effects*
  • Intestines/microbiology
  • Vascular Endothelial Growth Factor A/metabolism
  • Atrial Natriuretic Factor/metabolism
  • Bacterial Proteins/toxicity*
  • Serum Albumin, Human/metabolism
  • Cardiovascular Diseases/chemically induced
  • Cardiovascular Diseases/metabolism
(all 28)
PubMed
33271969 Full text @ Cells
Abstract
C.difficile infection (CDI) is not a merely "gut-confined" disease as toxemia could drive the development of CDI-related extra-intestinal effects. These effects could explain the high CDI-associated mortality, not just justified by diarrhea and dehydration. Here, the extra-intestinal effects of toxin A (TcdA) and B (TcdB) produced by C. difficile have been studied in vivo using the zebrafish embryo model. Noteworthy, protective properties of human serum albumin (HSA) towards toxins-induced extra-intestinal effects were also addressed. Zebrafish embryos were treated with TcdA, TcdB and/or HSA at 24 h post-fertilization. Embryos were analyzed for 48 h after treatment to check vital signs and morphological changes. Markers related to cardio-vascular damage and inflammation were evaluated by Real-Time quantitative PCR and/or western blotting. Both toxins induced cardiovascular damage in zebrafish embryos by different mechanisms: (i) direct toxicity (i.e., pericardial edema, cardiac chambers enlargement, endothelial alteration); (ii) increased hormonal production and release (i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), (iii) alteration of the vascular system through the increase of the vascular endothelial growth factor (VEGF-A) levels, as well as of its receptors, (iv) pro-inflammatory response through high cytokines production (i.e., CXCL8, IL1B, IL6 and TNFα) and (v) cell-mediated damage due to the increase in neutrophils number. In addition to cardiovascular damage, we observe skin alteration and inflammation. Finally, our data indicate a protective effect of HSA toward the toxins induced extra-intestinal effects. Together, our findings can serve as a starting point for humans' studies to substantiate and understand the extra-intestinal effects observed in CDI patients.
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Citation
Tonon, F., Di Bella, S., Grassi, G., Luzzati, R., Ascenzi, P., di Masi, A., Zennaro, C. (2020) Extra-Intestinal Effects of C.difficile Toxin A and B: An In Vivo Study Using the Zebrafish Embryo Model. Cells. 9(12):.