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dc.contributor.authorValmas, Charalamposen_US
dc.contributor.authorGrosch, Melanie N.en_US
dc.contributor.authorSchümann, Michaelen_US
dc.contributor.authorOlejnik, Judithen_US
dc.contributor.authorMartinez, Osvaldoen_US
dc.contributor.authorBest, Sonja M.en_US
dc.contributor.authorKrähling, Verenaen_US
dc.contributor.authorBasler, Christopher F.en_US
dc.contributor.authorMühlberger, Elkeen_US
dc.date.accessioned2012-01-11T23:26:27Z
dc.date.available2012-01-11T23:26:27Z
dc.date.issued2010-1-15en_US
dc.identifier.citationValmas, Charalampos, Melanie N. Grosch, Michael Schümann, Judith Olejnik, Osvaldo Martinez, Sonja M. Best, Verena Krähling, Christopher F. Basler, Elke Mühlberger. "Marburg Virus Evades Interferon Responses by a Mechanism Distinct from Ebola Virus" PLoS Pathogens 6(1): e1000721. (2010)en_US
dc.identifier.issn1553-7374en_US
dc.identifier.urihttp://hdl.handle.net/2144/3350
dc.description.abstractPrevious studies have demonstrated that Marburg viruses (MARV) and Ebola viruses (EBOV) inhibit interferon (IFN)-α/β signaling but utilize different mechanisms. EBOV inhibits IFN signaling via its VP24 protein which blocks the nuclear accumulation of tyrosine phosphorylated STAT1. In contrast, MARV infection inhibits IFN/α/β induced tyrosine phosphorylation of STAT1 and STAT2. MARV infection is now demonstrated to inhibit not only IFNα/β but also IFNγ-induced STAT phosphorylation and to inhibit the IFNα/β and IFNγ-induced tyrosine phosphorylation of upstream Janus (Jak) family kinases. Surprisingly, the MARV matrix protein VP40, not the MARV VP24 protein, has been identified to antagonize Jak and STAT tyrosine phosphorylation, to inhibit IFNα/β or IFNγ-induced gene expression and to inhibit the induction of an antiviral state by IFNα/β. Global loss of STAT and Jak tyrosine phosphorylation in response to both IFNa/α/β and IFNγ is reminiscent of the phenotype seen in Jak1-null cells. Consistent with this model, MARV infection and MARV VP40 expression also inhibit the Jak1-dependent, IL-6-induced tyrosine phosphorylation of STAT1 and STAT3. Finally, expression of MARV VP40 is able to prevent the tyrosine phosphorylation of Jak1, STAT1, STAT2 or STAT3 which occurs following over-expression of the Jak1 kinase. In contrast, MARV VP40 does not detectably inhibit the tyrosine phosphorylation of STAT2 or Tyk2 when Tyk2 is over-expressed. Mutation of the VP40 late domain, essential for efficient VP40 budding, has no detectable impact on inhibition of IFN signaling. This study shows that MARV inhibits IFN signaling by a mechanism different from that employed by the related EBOV. It identifies a novel function for the MARV VP40 protein and suggests that MARV may globally inhibit Jak1-dependent cytokine signaling. Author SummaryThe closely related members of the filovirus family, Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic disease in humans with high fatality rates. Infected individuals exhibit dysregulated immune responses which appear to result from several factors, including virus-mediated impairment of innate immune responses. Previous studies demonstrated that both MARV and EBOV block the type I interferon-induced Jak-STAT signaling pathway. For EBOV, the viral protein VP24 mediates the inhibitory effects by interfering with the nuclear translocation of activated STAT proteins. Here, we show that MARV uses a distinct mechanism to block IFN signaling pathways. Our data revealed that MARV blocks the phosphorylation of Janus kinases and their target STAT proteins in response to type I and type II interferon and interleukin 6. Surprisingly, the observed inhibition is not achieved by the MARV VP24 protein, but by the matrix protein VP40 which also mediates viral budding. Over-expression studies indicate that MARV VP40 globally antagonizes Jak1-dependent signaling. Further, we show that a MARV VP40 mutant defective for budding retains interferon antagonist function. Our results highlight a basic difference between EBOV and MARV, define a new function for MARV VP40 and reveal new targets for the development of anti-MARV therapies.en_US
dc.description.sponsorshipGerman Research Foundation (SFB 535);Boston University; National Institutes of Health (AI059536, AI057158); Northeast Biodefense Center-Lipkin; National Institutes of Health, National Institute of Allergy and Infectious Diseasesen_US
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.en_US
dc.titleMarburg Virus Evades Interferon Responses by a Mechanism Distinct from Ebola Virusen_US
dc.typearticleen_US
dc.identifier.doi10.1371/journal.ppat.1000721en_US
dc.identifier.pubmedid20084112en_US
dc.identifier.pmcid2799553en_US


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