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 journalArticle

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

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Keywords

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

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Yang, G., Pillich, H., White, R., Czikora, I., Pochic, I., Yue, Q., Hudel, M., Gorshkov, B. A., Verin, A. D., Sridhar, S., Isales, C. M., Eaton, D. C., Hamacher, J., Chakraborty, T., & Lucas, R. (2018). Listeriolysin O causes ENaC dysfunction in human airway epithelial cells. Toxins, 10(2), [79]. https://doi.org/10.3390/toxins10020079