Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection
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Ploegh_Evasion of innate.pdf
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Author(s)
Sun, Chenglong
Schattgen, Stefan A.
Pisitkun, Prapaporn
Jorgensen, Joan P.
Hilterbrand, Adam T.
Wang, Lucas J.
West, John A.
Hansen, Kathrine
Horan, Kristy A.
Jakobsen, Martin R.
Date Issued
February 2015
Journal
The Journal of Immunology
Publisher
American Association of Immunologists
Citation
Sun, Chenglong et al. “Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection.” The Journal of Immunology 194.4 (2015): 1819–1831.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.4049/jimmunol.1402495
