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Toxins 2018, 10(2), 79; https://doi.org/10.3390/toxins10020079

Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells

1
Vascular Biology Center, Medical College of Georgia at Augusta University, Room CB-3213B, Augusta, GA 30912-2500, USA
2
Institute of Medical Microbiology, Justus-Liebig University Giessen, 35392 Gießen, Germany
3
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Room CB-3213B, Augusta, GA 30912-2500, USA
4
Department of Biomedical Sciences, Georgia Campus-Philadelphia College of Osteopathic Medicine, Atlanta, GA 30224, USA
5
Biochemical Pharmacology, University of Konstanz, 78464 Konstanz, Germany
6
Sandoz Inc., 83607 Holzkirchen, Germany
7
Department of Physiology, Emory School of Medicine, Atlanta, GA 30307, USA
8
Department of Medicine, Medical College of Georgia, Augusta, GA 30901, USA
9
Department of Pneumology, Lindenhofspital, 3001 Bern, Switzerland
10
Internal, Pulmonary and Critical Care Medicine, Saarland University, 66424 Homburg/Saar, Germany
11
Lungen-und Atmungsstifung, 3001 Bern, Switzerland
*
Authors to whom correspondence should be addressed.
Received: 22 December 2017 / Revised: 1 February 2018 / Accepted: 7 February 2018 / Published: 11 February 2018
(This article belongs to the Section Bacterial Toxins)
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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. View Full-Text
Keywords: listeriolysin O; TNF; pulmonary permeability edema; epithelial sodium channel; protein kinase C-α listeriolysin O; TNF; pulmonary permeability edema; epithelial sodium channel; protein kinase C-α
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Yang, G.; Pillich, H.; White, R.; Czikora, I.; Pochic, I.; Yue, Q.; Hudel, M.; Gorshkov, B.; Verin, A.; Sridhar, S.; Isales, C.M.; Eaton, D.C.; Hamacher, J.; Chakraborty, T.; Lucas, R. Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells. Toxins 2018, 10, 79.

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