title: Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection.
abstract: 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.
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, DK-8000 Aarhus C, Denmark;
authors.forename: Chenglong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Schattgen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, DK-8000 Aarhus C, Denmark; Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 10400;
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Pisitkun
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, DK-8000 Aarhus C, Denmark;
authors.forename: Joan P
authors.initials: JP
authors.lastname: Jorgensen
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712;
authors.forename: Adam T
authors.initials: AT
authors.lastname: Hilterbrand
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712;
authors.forename: Lucas J
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599;
authors.forename: John A
authors.initials: JA
authors.lastname: West
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, DK-8000 Aarhus C, Denmark;
authors.forename: Kathrine
authors.initials: K
authors.lastname: Hansen
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark;
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Horan
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, DK-8000 Aarhus C, Denmark;
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.affiliation: Section of Virology, Faculty of Medicine, Imperial College, St. Mary's Campus, London W2 1PG, United Kingdom;
authors.forename: Peter
authors.initials: P
authors.lastname: O'Hare
authors.affiliation: Helmholtz Zentrum Munich, German Research Center for Environmental Health, D-81377 Munich, Germany;
authors.forename: Heiko
authors.initials: H
authors.lastname: Adler
authors.affiliation: Department of Molecular Biology and Medical Pharmacology, Faculty of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Ren
authors.initials: R
authors.lastname: Sun
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712;
authors.forename: Jason W
authors.initials: JW
authors.lastname: Upton
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Aarhus Research Center for Innate Immunology, Aarhus University, DK-8000 Aarhus C, Denmark; srp@biomed.au.dk.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
mesh_terms: D000818:Animals; D003600:Cytosol / Q000276:immunology; D004279:DNA, Viral / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018142:Gammaherpesvirinae / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D017735:Virus Latency / Q000276:immunology*
chemical_list: D004279:DNA, Viral