Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells

Toxins (Basel). 2018 Feb 11;10(2):79. doi: 10.3390/toxins10020079.


Pulmonary permeability edema is characterized by reduced alveolar Na⁺ uptake capacity and capillary barrier dysfunction and is a potentially lethal complication of listeriosis. Apical Na⁺ uptake is mainly mediated by the epithelial sodium channel (ENaC) and initiates alveolar liquid clearance. Here we examine how listeriolysin O (LLO), the pore-forming toxin of Listeria monocytogenes, impairs the expression and activity of ENaC. To that purpose, we studied how sub-lytic concentrations of LLO affect negative and positive regulators of ENaC expression in the H441 airway epithelial cell line. LLO reduced expression of the crucial ENaC-α subunit in H441 cells within 2 h and this was preceded by activation of PKC-α, a negative regulator of the channel's expression. At later time points, LLO caused a significant reduction in the phosphorylation of Sgk-1 at residue T256 and of Akt-1 at residue S473, both of which are required for full activation of ENaC. The TNF-derived TIP peptide prevented LLO-mediated PKC-α activation and restored phospho-Sgk-1-T256. The TIP peptide also counteracted the observed LLO-induced decrease in amiloride-sensitive Na⁺ current and ENaC-α expression in H441 cells. Intratracheally instilled LLO caused profound pulmonary edema formation in mice, an effect that was prevented by the TIP peptide; thus indicating the therapeutic potential of the peptide for the treatment of pore-forming toxin-associated permeability edema.

Keywords: TNF; epithelial sodium channel; listeriolysin O; protein kinase C-α; pulmonary permeability edema.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / toxicity*
  • Bronchi / cytology
  • Cell Line
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology
  • Epithelial Sodium Channels / physiology*
  • Heat-Shock Proteins / toxicity*
  • Hemolysin Proteins / toxicity*
  • Humans
  • Immediate-Early Proteins / metabolism
  • Male
  • Mice, Inbred C57BL
  • Peptides / pharmacology*
  • Peptides / therapeutic use*
  • Phosphorylation / drug effects
  • Protein Kinase C-alpha / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Edema / drug therapy*


  • Bacterial Toxins
  • Epithelial Sodium Channels
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • Immediate-Early Proteins
  • Peptides
  • pepBs1-Ac peptide
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • serum-glucocorticoid regulated kinase
  • PRKCA protein, human
  • Protein Kinase C-alpha
  • hlyA protein, Listeria monocytogenes