{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T06:27:11Z","timestamp":1789885631943,"version":"4.0.1"},"reference-count":69,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T00:00:00Z","timestamp":1464048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,7,6]],"date-time":"2016-07-06T00:00:00Z","timestamp":1467763200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI108735"],"award-info":[{"award-number":["R01 AI108735"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI123348"],"award-info":[{"award-number":["R01 AI123348"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U54 AI057157"],"award-info":[{"award-number":["U54 AI057157"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["T32 HL07751"],"award-info":[{"award-number":["T32 HL07751"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2016,7,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>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.<\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            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.\n          <\/jats:p>","DOI":"10.1128\/mbio.00693-16","type":"journal-article","created":{"date-parts":[[2016,5,25]],"date-time":"2016-05-25T01:13:40Z","timestamp":1464138820000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":71,"title":["Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection"],"prefix":"10.1128","volume":"7","author":[{"given":"Alison W.","family":"Ashbrook","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Lentscher","sequence":"additional","affiliation":[{"name":"Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula F.","family":"Zamora","sequence":"additional","affiliation":[{"name":"Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie A.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"May","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Vanderbilt Institute of Chemical Biology, High-Throughput Screening Facility, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence S.","family":"Dermody","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"},{"name":"Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD\/0b013e31806010a5"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61779-6"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1606.091115"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1705.101873"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60185-9"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES2014.19.13.20759"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60281-X"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.64"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268808001167"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/517537"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2009.06.027"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1086\/590003"},{"key":"e_1_3_2_14_2","first-page":"26","article-title":"Burden of chikungunya in India: estimates of disability adjusted life years (DALY) lost in 2006 epidemic","volume":"46","author":"Krishnamoorthy K","year":"2009","unstructured":"Krishnamoorthy K, Harichandrakumar KT, Krishna Kumari A, Das LK. 2009. Burden of chikungunya in India: estimates of disability adjusted life years (DALY) lost in 2006 epidemic. J Vector Borne Dis 46:26\u201335.","journal-title":"J Vector Borne Dis"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007800"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001197"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.51.1.254-258.1984"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0030089"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011479"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09546"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2040796"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-83-12-3075"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2009.07.024"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.10.3.504-515.1972"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.6.2075"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-10-169"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.8.3873-3884.2001"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01441-10"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00477-10"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01467-12"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00739-15"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041270202"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3039660"},{"key":"e_1_3_2_34_2","first-page":"195","article-title":"Determinants of human and mouse melanoma cell sensitivities to oleandrin","volume":"7","author":"Lin Y","year":"2008","unstructured":"Lin Y, Dubinsky WP, Ho DH, Felix E, Newman RA. 2008. Determinants of human and mouse melanoma cell sensitivities to oleandrin. J Exp Ther Oncol 7:195\u2013205.","journal-title":"J Exp Ther Oncol"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201107200"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-45-1-161"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.61.8.2351-2361.1987"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02056-10"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2004.03.009"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002719"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr859"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00231-8"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002383"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01579-15"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.12.010"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00439-14"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03612-14"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.2165\/00129784-200707030-00004"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207847200"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.10.3.537-544.1972"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221315298"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005080894"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.909001"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001813-200106000-00009"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi048680w"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2007.03.013"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09978"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200010)43:10<2152::AID-ANR2>3.0.CO;2-R"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01672-14"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(97)00036-2"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004680200"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.06.009"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00405-13"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.62.6.2124-2133.1988"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(91)90584-X"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01495-08"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.62.12.4594-4604.1988"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.62.1.246-256.1988"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(69)90017-8"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.18.8268-8276.2000"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00693-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00693-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T02:01:39Z","timestamp":1646704899000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.00693-16"}},"subtitle":[],"editor":[{"given":"Anne","family":"Moscona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,7,6]]},"references-count":69,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2016,7,6]]}},"alternative-id":["10.1128\/mBio.00693-16"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00693-16","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,6]]},"assertion":[{"value":"2016-04-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00693-16"}}