Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Cytosol; DNA, Viral; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gammaherpesvirinae; Herpesviridae Infections; Humans; Immunity, Innate; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Real-Time Polymerase Chain Reaction; Virus Latency
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 alpha- and beta-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.
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Citation: J Immunol. 2015 Feb 15;194(4):1819-31. doi: 10.4049/jimmunol.1402495. Link to article on publisher's site
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.; and Paludan, Soren R., "Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection" (2015). Infectious Diseases and Immunology Publications and Presentations. 192.