Evasion of Innate Cytosolic DNA Sensing by a Gammaherpesvirus Facilitates Establishment of Latent Infection
Year: 2015
Type: article
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.
Source: The Journal of Immunology
Authors: 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
Institutions: Aarhus University, University of Massachusetts Chan Medical School, Mahidol University, Ramathibodi Hospital, The University of Texas at Austin, University of North Carolina at Chapel Hill, Imperial College London, Helmholtz Munich, University of California, Los Angeles, Whitehead Institute for Biomedical Research
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1694141453, Discovery of New Innate Immune Pathways in Viral Recognition, G3860392808, DNA sensors and associated signaling pathways in the innate immune response, Innate Immunity and KSHV, G5331442387, G5668739698, G604311963, Characterization of novel genes encoded ty RNA and DNA viruses, G6845008427, Role of PISA; a PYHIN Family Member in Intracellular DNA Recognition, Training in Immunology and Microbiology, Reactivation of Kaposi's Sarcoma-Associated Herpesvirus, Innate Immunity Training Program, Viral Oncogenesis, Latency, and Replication, Cancer Center Support Grant
OpenAlex ID: W1629500030