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Article: Influenza virus non-structural protein 1 (NS1) disrupts interferon signaling

TitleInfluenza virus non-structural protein 1 (NS1) disrupts interferon signaling
Authors
Issue Date2010
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2010, v. 5 n. 11 How to Cite?
AbstractType I interferons (IFNs) function as the first line of defense against viral infections by modulating cell growth, establishing an antiviral state and influencing the activation of various immune cells. Viruses such as influenza have developed mechanisms to evade this defense mechanism and during infection with influenza A viruses, the non-structural protein 1 (NS1) encoded by the virus genome suppresses induction of IFNs-α/β. Here we show that expression of avian H5N1 NS1 in HeLa cells leads to a block in IFN signaling. H5N1 NS1 reduces IFN-inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibits the nuclear translocation of phospho-STAT2 and the formation of IFN-inducible STAT1:1-, STAT1:3- and STAT3:3- DNA complexes. Inhibition of IFN-inducible STAT signaling by NS1 in HeLa cells is, in part, a consequence of NS1-mediated inhibition of expression of the IFN receptor subunit, IFNAR1. In support of this NS1-mediated inhibition, we observed a reduction in expression of ifnar1 in ex vivo human non-tumor lung tissues infected with H5N1 and H1N1 viruses. Moreover, H1N1 and H5N1 virus infection of human monocyte-derived macrophages led to inhibition of both ifnar1 and ifnar2 expression. In addition, NS1 expression induces up-regulation of the JAK/STAT inhibitors, SOCS1 and SOCS3. By contrast, treatment of ex vivo human lung tissues with IFN-α results in the up-regulation of a number of IFN-stimulated genes and inhibits both H5N1 and H1N1 virus replication. The data suggest that NS1 can directly interfere with IFN signaling to enhance viral replication, but that treatment with IFN can nevertheless override these inhibitory effects to block H5N1 and H1N1 virus infections. © 2010 Jia et al.
Persistent Identifierhttp://hdl.handle.net/10722/135254
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Canadian Institutes of Health ResearchMOP-15094
Public Health Agency of Canada
Research Funds for the Control of Infectious Diseases10090202
University Grants Committee of the Hong Kong Special Administrative Region, ChinaAoE/M-12/-06
Funding Information:

These studies were supported by a Canadian Institutes of Health Research grant (MOP-15094) and a Public Health Agency of Canada grant to E.N.F., Research Funds for the Control of Infectious Diseases grant to J.M.N. (10090202) and funding to R.W.Y.C., M.C.W.C. and J.S.M.P. from the Area of Excellence Scheme of the University Grants Committee (grant AoE/M-12/-06 of the Hong Kong Special Administrative Region, China). D.J. and R.R. are recipients of Canadian Institutes of Health Research scholarship awards. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. D.P.B. is employed by Biogen Idec, thus Biogen Idec did have a role in providing IFN-beta and in the review and editing of the manuscript.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorJia, Den_HK
dc.contributor.authorRahbar, Ren_HK
dc.contributor.authorChan, RWYen_HK
dc.contributor.authorLee, SMYen_HK
dc.contributor.authorChan, MCWen_HK
dc.contributor.authorWang, BXen_HK
dc.contributor.authorBaker, DPen_HK
dc.contributor.authorSun, Ben_HK
dc.contributor.authorMalik Peiris, JSen_HK
dc.contributor.authorNicholls, JMen_HK
dc.contributor.authorFish, ENen_HK
dc.date.accessioned2011-07-27T01:30:43Z-
dc.date.available2011-07-27T01:30:43Z-
dc.date.issued2010en_HK
dc.identifier.citationPlos One, 2010, v. 5 n. 11en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135254-
dc.description.abstractType I interferons (IFNs) function as the first line of defense against viral infections by modulating cell growth, establishing an antiviral state and influencing the activation of various immune cells. Viruses such as influenza have developed mechanisms to evade this defense mechanism and during infection with influenza A viruses, the non-structural protein 1 (NS1) encoded by the virus genome suppresses induction of IFNs-α/β. Here we show that expression of avian H5N1 NS1 in HeLa cells leads to a block in IFN signaling. H5N1 NS1 reduces IFN-inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibits the nuclear translocation of phospho-STAT2 and the formation of IFN-inducible STAT1:1-, STAT1:3- and STAT3:3- DNA complexes. Inhibition of IFN-inducible STAT signaling by NS1 in HeLa cells is, in part, a consequence of NS1-mediated inhibition of expression of the IFN receptor subunit, IFNAR1. In support of this NS1-mediated inhibition, we observed a reduction in expression of ifnar1 in ex vivo human non-tumor lung tissues infected with H5N1 and H1N1 viruses. Moreover, H1N1 and H5N1 virus infection of human monocyte-derived macrophages led to inhibition of both ifnar1 and ifnar2 expression. In addition, NS1 expression induces up-regulation of the JAK/STAT inhibitors, SOCS1 and SOCS3. By contrast, treatment of ex vivo human lung tissues with IFN-α results in the up-regulation of a number of IFN-stimulated genes and inhibits both H5N1 and H1N1 virus replication. The data suggest that NS1 can directly interfere with IFN signaling to enhance viral replication, but that treatment with IFN can nevertheless override these inhibitory effects to block H5N1 and H1N1 virus infections. © 2010 Jia et al.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshInfluenza A virus - genetics - metabolism - physiology-
dc.subject.meshInterferons - metabolism - pharmacology-
dc.subject.meshLung - drug effects - metabolism - virology-
dc.subject.meshSignal Transduction - physiology-
dc.subject.meshViral Nonstructural Proteins - genetics - metabolism - physiology-
dc.titleInfluenza virus non-structural protein 1 (NS1) disrupts interferon signalingen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, RWY: reneewy@hku.hken_HK
dc.identifier.emailLee, SMY: suki@hku.hken_HK
dc.identifier.emailChan, MCW: mchan@hku.hken_HK
dc.identifier.emailMalik Peiris, JS: malik@hkucc.hku.hken_HK
dc.identifier.emailNicholls, JM: jmnichol@hkucc.hku.hken_HK
dc.identifier.authorityChan, RWY=rp01596en_HK
dc.identifier.authorityLee, SMY=rp01536en_HK
dc.identifier.authorityChan, MCW=rp00420en_HK
dc.identifier.authorityMalik Peiris, JS=rp00410en_HK
dc.identifier.authorityNicholls, JM=rp00364en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0013927en_HK
dc.identifier.pmid21085662-
dc.identifier.pmcidPMC2978095-
dc.identifier.scopuseid_2-s2.0-78649732404en_HK
dc.identifier.hkuros186635en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78649732404&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume5en_HK
dc.identifier.issue11en_HK
dc.identifier.spagee13927en_US
dc.identifier.epagee13927en_US
dc.identifier.isiWOS:000284036800018-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectPrevention and treatment of swine origin influenza virus (S-OIV) though the use of interferon - an in vivo and ex vivo study-
dc.identifier.scopusauthoridJia, D=17345382100en_HK
dc.identifier.scopusauthoridRahbar, R=14034785300en_HK
dc.identifier.scopusauthoridChan, RWY=26661379100en_HK
dc.identifier.scopusauthoridLee, SMY=35435155600en_HK
dc.identifier.scopusauthoridChan, MCW=26654715500en_HK
dc.identifier.scopusauthoridWang, BX=36994068500en_HK
dc.identifier.scopusauthoridBaker, DP=7404140675en_HK
dc.identifier.scopusauthoridSun, B=24734369900en_HK
dc.identifier.scopusauthoridMalik Peiris, JS=7005486823en_HK
dc.identifier.scopusauthoridNicholls, JM=7201463077en_HK
dc.identifier.scopusauthoridFish, EN=7005707926en_HK
dc.identifier.citeulike8337979-

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