Listeriolysin O causes ENaC dysfunction in human airway epithelial cells

Guang Yang, Helena Pillich, Richard White, Istvan Czikora, Isabelle Pochic, Qiang Yue, Martina Hudel, Boris A Gorshkov, Alexander Dmitriyevich Verin, Supriya Sridhar, Carlos M Isales, Douglas C. Eaton, Jürg Hamacher, Trinad Chakraborty, Rudolf Lucas

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number79
JournalToxins
Volume10
Issue number2
DOIs
StatePublished - Feb 11 2018

Keywords

  • Epithelial sodium channel
  • Listeriolysin O
  • Protein kinase C-α
  • Pulmonary permeability edema
  • TNF

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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