Chenglong SunStefan A. SchattgenPrapaporn PisitkunJoan P. JorgensenAdam T. HilterbrandLucas J. WangJohn A. WestKathrine HansenKristy A. HoranMartin R. JakobsenPeter O'HareHeiko AdlerRen SunHidde L. PloeghBlossom DamaniaJason W. UptonKatherine A. FitzgeraldSøren R. PaludanAarhus UniversitetUniversity of Massachusetts Medical SchoolMahidol UniversityUniversity of Texas at AustinThe University of North Carolina at Chapel HillImperial College LondonHelmholtz Center Munich German Research Center for Environmental HealthUniversity of California, Los AngelesWhitehead Institute for Biomedical Research2018-11-232018-11-232015-02-15Journal of Immunology. Vol.194, No.4 (2015), 1819-183115506606002217672-s2.0-84922513904https://repository.li.mahidol.ac.th/handle/20.500.14594/36126Copyright © 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.Mahidol UniversityImmunology and MicrobiologyArticleSCOPUS10.4049/jimmunol.1402495