Title

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

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

2-15-2015

Document Type

Article

Subjects

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

Disciplines

Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease | Virology | Virus Diseases

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.

Rights and Permissions

Citation: J Immunol. 2015 Feb 15;194(4):1819-31. doi: 10.4049/jimmunol.1402495. Link to article on publisher's site

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

Related Resources

Link to Article in PubMed

PubMed ID

25595793