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Sun, C.* ; Schattgen, S.A.* ; Pisitkun, P.* ; Jorgensen, J.P.* ; Hilterbrand, A.T.* ; Wang, L.J.* ; West, J.A.* ; Hansen, K.* ; Horan, K.A.* ; Jakobsen, M.R.* ; O'Hare, P.* ; Adler, H. ; Sun, R.* ; Ploegh, H.L.* ; Damania, B.* ; Upton, J.W.* ; Fitzgerald, K.A.* ; Paludan, S.R.*

Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection.

J. Immunol. 194, 1819-1831 (2015)
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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 α- and β-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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Sarcoma-associated Herpesvirus; Plasmacytoid Dendritic Cells; Bacterial Artificial Chromosome; I Interferon Response; Intracellular Dna; Tlr9 Contributes; Recognition; Ifi16; Immunity; Protein
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 0022-1767
e-ISSN 1550-6606
Journal Journal of Immunology
Quellenangaben Volume: 194, Issue: 4, Pages: 1819-1831 Article Number: , Supplement: ,
Publisher American Association of Immunologists
Publishing Place Bethesda
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-501500-006
PubMed ID 25595793
DOI 10.4049/jimmunol.1402495
WOS ID WOS:000349462000045
Erfassungsdatum 2015-01-19
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