Cardiac glycosides decrease influenza virus replication by inhibiting cell protein translational machinery

• Published in: American journal of physiology. Lung cellular and molecular physiology 2019-06, Vol.316 (6), p.L1094-L1106
• Main Authors: Amarelle, Luciano, Katzen, Jeremy, Shigemura, Masahiko, Welch, Lynn C, Cajigas, Héctor, Peteranderl, Christin, Celli, Diego, Herold, Susanne, Lecuona, Emilia, Sznajder, Jacob I
• Format: Article
• Language: English
• Subjects: A549 Cells; Alveolar Epithelial Cells - virology; Alveoli; Animals; Antiviral Agents - pharmacology; Calcium; Calcium (intracellular); Cardiac glycosides; Cardiac Glycosides - pharmacology; Cell Line, Tumor; Cytotoxicity; Dogs; Enzyme Inhibitors - pharmacology; Epithelial cells; Female; Glycosides; Humans; Influenza; Influenza A; Influenza A virus; Influenza, Human - drug therapy; Inhibition; Intracellular; Intracellular signalling; Lung - virology; Lungs; Machinery and equipment; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Inbred C57BL; Na+/K+-exchanging ATPase; Ouabain; Ouabain - pharmacology; Potassium; Potassium - metabolism; Protein Biosynthesis - physiology; Proteins; Replication; Rodents; Signal transduction; Sodium; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Survival; Toxicity; Transcription; Translation; Virus Replication - physiology; Viruses
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00173.2018

Cardiac glycosides (CGs) are used primarily for cardiac failure and have been reported to have other effects, including inhibition of viral replication. Here we set out to study mechanisms by which CGs as inhibitors of the Na-K-ATPase decrease influenza A virus (IAV) replication in the lungs. We found that CGs inhibit influenza virus replication in alveolar epithelial cells by decreasing intracellular potassium, which in turn inhibits protein translation, independently of viral entry, mRNA transcription, and protein degradation. These effects were independent of the Src signaling pathway and intracellular calcium concentration changes. We found that short-term treatment with ouabain prevented IAV replication without cytotoxicity. Rodents express a Na-K-ATPase-α1 resistant to CGs. Thus we utilized Na-K-ATPase-α -sensitive mice, infected them with high doses of influenza virus, and observed a modest survival benefit when treated with ouabain. In summary, we provide evidence that the inhibition of the Na-K-ATPase by CGs decreases influenza A viral replication by modulating the cell protein translational machinery and results in a modest survival benefit in mice.