Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection

ABSTRACT Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We conducted a high-throughput, chemical compo...

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Autores principales:	Alison W. Ashbrook, Anthony J. Lentscher, Paula F. Zamora, Laurie A. Silva, Nicholas A. May, Joshua A. Bauer, Thomas E. Morrison, Terence S. Dermody
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/14d88177dc7140fe8068a099bec59762
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spelling	oai:doaj.org-article:14d88177dc7140fe8068a099bec597622021-11-15T15:50:17ZAntagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection10.1128/mBio.00693-162150-7511https://doaj.org/article/14d88177dc7140fe8068a099bec597622016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00693-16https://doaj.org/toc/2150-7511ABSTRACT Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We conducted a high-throughput, chemical compound screen that identified digoxin, a cardiac glycoside that blocks the sodium-potassium ATPase, as a potent inhibitor of CHIKV infection. Treatment of human cells with digoxin or a related cardiac glycoside, ouabain, resulted in a dose-dependent decrease in infection by CHIKV. Inhibition by digoxin was cell type-specific, as digoxin treatment of either murine or mosquito cells did not diminish CHIKV infection. Digoxin displayed antiviral activity against other alphaviruses, including Ross River virus and Sindbis virus, as well as mammalian reovirus and vesicular stomatitis virus. The digoxin-mediated block to CHIKV and reovirus infection occurred at one or more postentry steps, as digoxin inhibition was not bypassed by fusion of CHIKV at the plasma membrane or infection with cell surface-penetrating reovirus entry intermediates. Selection of digoxin-resistant CHIKV variants identified multiple mutations in the nonstructural proteins required for replication complex formation and synthesis of viral RNA. These data suggest a role for the sodium-potassium ATPase in promoting postentry steps of CHIKV replication and provide rationale for modulation of this pathway as a broad-spectrum antiviral strategy. IMPORTANCE Mitigation of disease induced by globally spreading, mosquito-borne arthritogenic alphaviruses requires the development of new antiviral strategies. High-throughput screening of clinically tested compounds provides a rapid means to identify undiscovered, antiviral functions for well-characterized therapeutics and illuminate host pathways required for viral infection. Our study describes the potent inhibition of Chikungunya virus and related alphaviruses by the cardiac glycoside digoxin and demonstrates a function for the sodium-potassium ATPase in Chikungunya virus infection.Alison W. AshbrookAnthony J. LentscherPaula F. ZamoraLaurie A. SilvaNicholas A. MayJoshua A. BauerThomas E. MorrisonTerence S. DermodyAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Alison W. Ashbrook Anthony J. Lentscher Paula F. Zamora Laurie A. Silva Nicholas A. May Joshua A. Bauer Thomas E. Morrison Terence S. Dermody Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection
description	ABSTRACT Chikungunya virus (CHIKV) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. There are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. We conducted a high-throughput, chemical compound screen that identified digoxin, a cardiac glycoside that blocks the sodium-potassium ATPase, as a potent inhibitor of CHIKV infection. Treatment of human cells with digoxin or a related cardiac glycoside, ouabain, resulted in a dose-dependent decrease in infection by CHIKV. Inhibition by digoxin was cell type-specific, as digoxin treatment of either murine or mosquito cells did not diminish CHIKV infection. Digoxin displayed antiviral activity against other alphaviruses, including Ross River virus and Sindbis virus, as well as mammalian reovirus and vesicular stomatitis virus. The digoxin-mediated block to CHIKV and reovirus infection occurred at one or more postentry steps, as digoxin inhibition was not bypassed by fusion of CHIKV at the plasma membrane or infection with cell surface-penetrating reovirus entry intermediates. Selection of digoxin-resistant CHIKV variants identified multiple mutations in the nonstructural proteins required for replication complex formation and synthesis of viral RNA. These data suggest a role for the sodium-potassium ATPase in promoting postentry steps of CHIKV replication and provide rationale for modulation of this pathway as a broad-spectrum antiviral strategy. IMPORTANCE Mitigation of disease induced by globally spreading, mosquito-borne arthritogenic alphaviruses requires the development of new antiviral strategies. High-throughput screening of clinically tested compounds provides a rapid means to identify undiscovered, antiviral functions for well-characterized therapeutics and illuminate host pathways required for viral infection. Our study describes the potent inhibition of Chikungunya virus and related alphaviruses by the cardiac glycoside digoxin and demonstrates a function for the sodium-potassium ATPase in Chikungunya virus infection.
format	article
author	Alison W. Ashbrook Anthony J. Lentscher Paula F. Zamora Laurie A. Silva Nicholas A. May Joshua A. Bauer Thomas E. Morrison Terence S. Dermody
author_facet	Alison W. Ashbrook Anthony J. Lentscher Paula F. Zamora Laurie A. Silva Nicholas A. May Joshua A. Bauer Thomas E. Morrison Terence S. Dermody
author_sort	Alison W. Ashbrook
title	Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection
title_short	Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection
title_full	Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection
title_fullStr	Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection
title_full_unstemmed	Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection
title_sort	antagonism of the sodium-potassium atpase impairs chikungunya virus infection
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/14d88177dc7140fe8068a099bec59762
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Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection

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