Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection
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. ... show 8 more
Citations
Authors
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, Soren R.
Student Authors
Faculty Advisor
Academic Program
UMass Chan Affiliations
Document Type
Publication Date
Keywords
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
Immunity
Immunology and Infectious Disease
Immunology of Infectious Disease
Infectious Disease
Virology
Virus Diseases
Subject Area
Embargo Expiration Date
Link to Full Text
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 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.
Source
J Immunol. 2015 Feb 15;194(4):1819-31. doi: 10.4049/jimmunol.1402495. Link to article on publisher's site