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

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

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1819-1831
Number of pages13
JournalJournal of Immunology
Volume194
Issue number4
DOIs
StatePublished - Feb 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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