The Antimicrobial Peptide CopA3 Inhibits Clostridium difficile Toxin A-Induced Viability Loss and Apoptosis in Neural Cells

J Microbiol Biotechnol. 2019 Jan 28;29(1):30-36. doi: 10.4014/jmb.1809.08065.

Abstract

Numerous studies have reported that enteric neurons involved in controlling neurotransmitter secretion and motility in the gut critically contribute to the progression of gut inflammation. Clostridium difficile toxins, which cause severe colonic inflammation, are also known to affect enteric neurons. Our previous study showed that C. difficile toxin A directly induces neural cell toxicities, such as viability loss and apoptosis. In the current study, we attempted to identify a potent inhibitor of toxin A-induced neural cell toxicity that may aid in managing toxin A-induced gut inflammation. In our recent study, we found that the Korea dung beetle-derived antimicrobial peptide CopA3 completely blocked neural cell apoptosis caused by okadaic acid or 6-OHDA. Here, we examined whether the antimicrobial peptide CopA3 inhibited toxin A-induced neural cell damage. In neuroblastoma SH-SY5Y cells, CopA3 treatment protected against both apoptosis and viability loss caused by toxin A. CopA3 also completely inhibited activation of the pro-apoptotic factor, caspase-3. Additionally, CopA3 rescued toxin A-induced downregulation of neural cell proliferation. However, CopA3 had no effect on signaling through ROS/p38 MAPK/p27kip1, suggesting that CopA3 inhibits toxin A-induced neural cell toxicity independent of this well-characterized toxin A pathway. Our data further suggest that ability of CopA3 to rescue toxin A-induced neural cell damage may also ameliorate the gut inflammation caused by toxin A.

Keywords: Bacterial toxin; apoptosis; enteric nerve system; gut inflammation; insect-derived antimicrobial peptide.

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / pharmacology*
  • Apoptosis / drug effects*
  • Bacterial Toxins / toxicity*
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects*
  • Clostridioides difficile / chemistry
  • Coleoptera / chemistry
  • Enterotoxins / toxicity*
  • Humans
  • Insect Proteins / genetics
  • Insect Proteins / pharmacology*
  • Mutation
  • Neurons / cytology*
  • Neurons / drug effects
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*

Substances

  • Antimicrobial Cationic Peptides
  • Bacterial Toxins
  • CopA3 peptide, Copris tripartitus
  • Enterotoxins
  • Insect Proteins
  • Neuroprotective Agents
  • tcdA protein, Clostridium difficile
  • CASP3 protein, human
  • Caspase 3