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Title: Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection
Authors: Chenglong Sun
Stefan A. Schattgen
Prapaporn Pisitkun
Joan P. Jorgensen
Adam T. Hilterbrand
Lucas J. Wang
John A. West
Kathrine Hansen
Kristy A. Horan
Martin R. Jakobsen
Peter O'Hare
Heiko Adler
Ren Sun
Hidde L. Ploegh
Blossom Damania
Jason W. Upton
Katherine A. Fitzgerald
Søren R. Paludan
Aarhus Universitet
University of Massachusetts Medical School
Mahidol University
University of Texas at Austin
The University of North Carolina at Chapel Hill
Imperial College London
Helmholtz Center Munich German Research Center for Environmental Health
University of California, Los Angeles
Whitehead Institute for Biomedical Research
Keywords: Immunology and Microbiology
Issue Date: 15-Feb-2015
Citation: Journal of Immunology. Vol.194, No.4 (2015), 1819-1831
Abstract: Copyright © 2015 by The American Association of Immunologists, Inc. 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.
ISSN: 15506606
Appears in Collections:Scopus 2011-2015

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