TY - JOUR
T1 - Cardiac glycosides decrease influenza virus replication by inhibiting cell protein translational machinery
AU - Amarelle, Luciano
AU - Katzen, Jeremy
AU - Shigemura, Masahiko
AU - Welch, Lynn C.
AU - Cajigas, Hector Rene
AU - Peteranderl, Christin
AU - Celli, Diego
AU - Herold, Susanne
AU - Lecuona, Emilia
AU - Sznajder, Jacob I.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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-α1-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.
AB - 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-α1-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.
KW - Na-K-ATPase
KW - antiviral treatment
KW - intracellular potassium
UR - http://www.scopus.com/inward/record.url?scp=85067270650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067270650&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00173.2018
DO - 10.1152/ajplung.00173.2018
M3 - Article
C2 - 30892074
AN - SCOPUS:85067270650
SN - 1040-0605
VL - 316
SP - L1094-L1106
JO - American journal of physiology. Lung cellular and molecular physiology
JF - American journal of physiology. Lung cellular and molecular physiology
IS - 6
ER -