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

Fingerprint

Epithelial Cells
Peptides
Chemical activation
Pulmonary Edema
Permeability
Listeria
Epithelial Sodium Channels
Listeriosis
Phosphorylation
Amiloride
Listeria monocytogenes
Listeria monocytogenes hlyA protein
Edema
Cell Line
Liquids

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

Listeriolysin O causes ENaC dysfunction in human airway epithelial cells. / Yang, Guang; Pillich, Helena; White, Richard; Czikora, Istvan; Pochic, Isabelle; Yue, Qiang; Hudel, Martina; Gorshkov, Boris A; Verin, Alexander Dmitriyevich; Sridhar, Supriya; Isales, Carlos M; Eaton, Douglas C.; Hamacher, Jürg; Chakraborty, Trinad; Lucas, Rudolf.

In: Toxins, Vol. 10, No. 2, 79, 11.02.2018.

Research output: Contribution to journalArticle

Yang, G, Pillich, H, White, R, Czikora, I, Pochic, I, Yue, Q, Hudel, M, Gorshkov, BA, Verin, AD, Sridhar, S, Isales, CM, Eaton, DC, Hamacher, J, Chakraborty, T & Lucas, R 2018, 'Listeriolysin O causes ENaC dysfunction in human airway epithelial cells', Toxins, vol. 10, no. 2, 79. https://doi.org/10.3390/toxins10020079
Yang, Guang ; Pillich, Helena ; White, Richard ; Czikora, Istvan ; Pochic, Isabelle ; Yue, Qiang ; Hudel, Martina ; Gorshkov, Boris A ; Verin, Alexander Dmitriyevich ; Sridhar, Supriya ; Isales, Carlos M ; Eaton, Douglas C. ; Hamacher, Jürg ; Chakraborty, Trinad ; Lucas, Rudolf. / Listeriolysin O causes ENaC dysfunction in human airway epithelial cells. In: Toxins. 2018 ; Vol. 10, No. 2.
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AU - Yang, Guang

AU - Pillich, Helena

AU - White, Richard

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AU - Pochic, Isabelle

AU - Yue, Qiang

AU - Hudel, Martina

AU - Gorshkov, Boris A

AU - Verin, Alexander Dmitriyevich

AU - Sridhar, Supriya

AU - Isales, Carlos M

AU - Eaton, Douglas C.

AU - Hamacher, Jürg

AU - Chakraborty, Trinad

AU - Lucas, Rudolf

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N2 - 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.

AB - 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.

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