Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection1

• Published in: The Journal of immunology (1950) 2015-01, Vol.194 (4), p.1819-1831
• Main Authors: 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., O'Hare, Peter, Adler, Heiko, Sun, Ren, Ploegh, Hidde L., Damania, Blossom, Upton, Jason W., Fitzgerald, Katherine A., Paludan, Søren R.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1402495

Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is currently limited knowledge on viruses targeting the innate DNA sensing pathway and also on how the innate system impacts on the latent reservoir of herpesvirus infections. Here we report that murine gammaherpesvirus MHV68, in contrast to alpha- and beta-herpesviruses, induce very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in control of MHV68 infections in vivo. Similarly, Kaposi's sarcoma-associated herpesvirus also did not stimulate immune signaling through the DNA sensing pathways. Interestingly, a MHV68 mutant lacking the deubiquitinase (DUB) activity, embedded within the large tegument protein ORF64, gained the capacity to stimulate the DNA-activated STING pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and AIM2 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.