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dc.contributor.authorSun, Chenglong
dc.contributor.authorSchattgen, Stefan A.
dc.contributor.authorPisitkun, Prapaporn
dc.contributor.authorJorgensen, Joan P.
dc.contributor.authorHilterbrand, Adam T.
dc.contributor.authorWang, Lucas J.
dc.contributor.authorWest, John A.
dc.contributor.authorHansen, Kathrine
dc.contributor.authorHoran, Kristy A.
dc.contributor.authorJakobsen, Martin R.
dc.contributor.authorO'Hare, Peter
dc.contributor.authorAdler, Heiko
dc.contributor.authorSun, Ren
dc.contributor.authorPloegh, Hidde L.
dc.contributor.authorDamania, Blossom
dc.contributor.authorUpton, Jason W.
dc.contributor.authorFitzgerald, Katherine A.
dc.contributor.authorPaludan, Soren R.
dc.date2022-08-11T08:09:09.000
dc.date.accessioned2022-08-23T16:19:07Z
dc.date.available2022-08-23T16:19:07Z
dc.date.issued2015-02-15
dc.date.submitted2015-04-27
dc.identifier.citationJ Immunol. 2015 Feb 15;194(4):1819-31. doi: 10.4049/jimmunol.1402495. <a href="http://dx.doi.org/10.4049/jimmunol.1402495">Link to article on publisher's site</a>
dc.identifier.issn0022-1767 (Linking)
dc.identifier.doi10.4049/jimmunol.1402495
dc.identifier.pmid25595793
dc.identifier.urihttp://hdl.handle.net/20.500.14038/34972
dc.description.abstractHerpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to alpha- and beta-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi's sarcoma-associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=25595793&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.4049/jimmunol.1402495
dc.subjectAnimals
dc.subjectCytosol
dc.subjectDNA, Viral
dc.subjectDisease Models, Animal
dc.subjectEnzyme-Linked Immunosorbent Assay
dc.subjectFlow Cytometry
dc.subjectGammaherpesvirinae
dc.subjectHerpesviridae Infections
dc.subjectHumans
dc.subjectImmunity, Innate
dc.subjectMacrophages
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectMicroscopy, Confocal
dc.subjectReal-Time Polymerase Chain Reaction
dc.subjectVirus Latency
dc.subjectImmunity
dc.subjectImmunology and Infectious Disease
dc.subjectImmunology of Infectious Disease
dc.subjectInfectious Disease
dc.subjectVirology
dc.subjectVirus Diseases
dc.titleEvasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection
dc.typeJournal Article
dc.source.journaltitleJournal of immunology (Baltimore, Md. : 1950)
dc.source.volume194
dc.source.issue4
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infdis_pp/192
dc.identifier.contextkey7036109
html.description.abstract<p>Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to alpha- and beta-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi's sarcoma-associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections.</p>
dc.identifier.submissionpathinfdis_pp/192
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages1819-31


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