2.50
Hdl Handle:
http://hdl.handle.net/10033/344188
Title:
Reversible silencing of cytomegalovirus genomes by type I interferon governs virus latency.
Authors:
Dağ, Franziska; Dölken, Lars; Holzki, Julia; Drabig, Anja; Weingärtner, Adrien; Schwerk, Johannes; Lienenklaus, Stefan; Conte, Ianina; Geffers, Robert ( 0000-0003-4409-016X ) ; Davenport, Colin; Rand, Ulfert; Köster, Mario; Weiß, Siegfried; Adler, Barbara; Wirth, Dagmar; Messerle, Martin; Hauser, Hansjörg; Cičin-Šain, Luka
Abstract:
Herpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE) genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN) limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blocks mouse CMV replication at the level of IE transcription in IFN-responding endothelial cells and fibroblasts. The IFN-mediated inhibition of IE genes was entirely reversible, arguing that the IFN-effect may be consistent with viral latency. Importantly, the response to IFNβ is stochastic, and MCMV IE transcription and replication were repressed only in IFN-responsive cells, while the IFN-unresponsive cells remained permissive for lytic MCMV infection. IFN blocked the viral lytic replication cycle by upregulating the nuclear domain 10 (ND10) components, PML, Sp100 and Daxx, and their knockdown by shRNA rescued viral replication in the presence of IFNβ. Finally, IFNβ prevented MCMV reactivation from endothelial cells derived from latently infected mice, validating our results in a biologically relevant setting. Therefore, our data do not only define for the first time the molecular mechanism of IFN-mediated control of CMV infection, but also indicate that the reversible inhibition of the virus lytic cycle by IFNβ is consistent with the establishment of CMV latency.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Citation:
Reversible silencing of cytomegalovirus genomes by type I interferon governs virus latency. 2014, 10 (2):e1003962 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Feb-2014
URI:
http://hdl.handle.net/10033/344188
DOI:
10.1371/journal.ppat.1003962
PubMed ID:
24586165
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the research group immune aging and chronic infections (IMCI)

Full metadata record

DC FieldValue Language
dc.contributor.authorDağ, Franziskaen
dc.contributor.authorDölken, Larsen
dc.contributor.authorHolzki, Juliaen
dc.contributor.authorDrabig, Anjaen
dc.contributor.authorWeingärtner, Adrienen
dc.contributor.authorSchwerk, Johannesen
dc.contributor.authorLienenklaus, Stefanen
dc.contributor.authorConte, Ianinaen
dc.contributor.authorGeffers, Roberten
dc.contributor.authorDavenport, Colinen
dc.contributor.authorRand, Ulferten
dc.contributor.authorKöster, Marioen
dc.contributor.authorWeiß, Siegfrieden
dc.contributor.authorAdler, Barbaraen
dc.contributor.authorWirth, Dagmaren
dc.contributor.authorMesserle, Martinen
dc.contributor.authorHauser, Hansjörgen
dc.contributor.authorCičin-Šain, Lukaen
dc.date.accessioned2015-02-04T15:27:22Zen
dc.date.available2015-02-04T15:27:22Zen
dc.date.issued2014-02en
dc.identifier.citationReversible silencing of cytomegalovirus genomes by type I interferon governs virus latency. 2014, 10 (2):e1003962 PLoS Pathog.en
dc.identifier.issn1553-7374en
dc.identifier.pmid24586165en
dc.identifier.doi10.1371/journal.ppat.1003962en
dc.identifier.urihttp://hdl.handle.net/10033/344188en
dc.description.abstractHerpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE) genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN) limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blocks mouse CMV replication at the level of IE transcription in IFN-responding endothelial cells and fibroblasts. The IFN-mediated inhibition of IE genes was entirely reversible, arguing that the IFN-effect may be consistent with viral latency. Importantly, the response to IFNβ is stochastic, and MCMV IE transcription and replication were repressed only in IFN-responsive cells, while the IFN-unresponsive cells remained permissive for lytic MCMV infection. IFN blocked the viral lytic replication cycle by upregulating the nuclear domain 10 (ND10) components, PML, Sp100 and Daxx, and their knockdown by shRNA rescued viral replication in the presence of IFNβ. Finally, IFNβ prevented MCMV reactivation from endothelial cells derived from latently infected mice, validating our results in a biologically relevant setting. Therefore, our data do not only define for the first time the molecular mechanism of IFN-mediated control of CMV infection, but also indicate that the reversible inhibition of the virus lytic cycle by IFNβ is consistent with the establishment of CMV latency.en
dc.language.isoenen
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/260934/en
dc.rightsopenAccessen
dc.subject.meshAnimalsen
dc.subject.meshCell Separationen
dc.subject.meshCytomegalovirusen
dc.subject.meshCytomegalovirus Infectionsen
dc.subject.meshDisease Models, Animalen
dc.subject.meshFluorescent Antibody Techniqueen
dc.subject.meshGene Expression Regulation, Viralen
dc.subject.meshGene Silencingen
dc.subject.meshGenes, Immediate-Earlyen
dc.subject.meshGenome, Viralen
dc.subject.meshHigh-Throughput Nucleotide Sequencingen
dc.subject.meshInterferon Type Ien
dc.subject.meshMiceen
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen
dc.subject.meshVirus Latencyen
dc.subject.meshVirus Replicationen
dc.titleReversible silencing of cytomegalovirus genomes by type I interferon governs virus latency.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.en
dc.identifier.journalPLoS pathogensen

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