Conserved gammaherpesvirus protein kinase counters myeloid cell-specific type I IFN receptor but not IRF-3 expression to promote the establishment of chronic latent infection in the spleen.

Authors

Erika R Johansen, Matthew A Brown, Xander G Bradeen, Cade R Rahlf, Daniela Avila, Damon L Schmalzriedt, Vera L Tarakanova

Published in

Journal of virology. Pages e0111026. Sep 01, 2026. Epub Sep 01, 2026.

Abstract

Gammaherpesviruses are prevalent pathogens that are associated with cancers and autoimmune diseases. All gammaherpesviruses encode a conserved protein kinase. Expression of orf36, the protein kinase encoded by murine gammaherpesvirus 68 (MHV68), supports the establishment of a latent viral reservoir in splenic B cells in vivo. Specifically, orf36 antagonizes myeloid cell-intrinsic STAT1 function to support the passage of MHV68 from myeloid cells to splenic B cells. STAT1 is a ubiquitously expressed transcription factor and a critical effector of interferon (IFN) antiviral functions. To define the extent to which the observed orf36-STAT1 antagonism reflected orf36 antagonism of the type I IFN axis, this study employed mouse models of myeloid cell-specific type I IFN receptor (IFNAR1) or interferon regulatory factor 3 (IRF-3) deficiencies. Myeloid cell-specific IFNAR1 deficiency resulted in the rescue of the attenuated splenic latent reservoir of the orf36 null MHV68, similar to that observed upon myeloid cell-specific STAT1 deficiency, refining the viral antagonism of the IFNAR1-STAT1 axis. However, and unlike that observed for IFNAR1, myeloid cell-specific deficiency of IRF-3, the transcription factor that drives type I IFN expression, failed to affect the attenuated chronic infection of the orf36 null MHV68 mutant. Unexpectedly, wild-type MHV68 reactivation in the spleen was attenuated in mice with myeloid cell-specific IRF-3 deficiency. Thus, the current study highlights a myeloid cell-specific antagonism between conserved gammaherpesvirus protein kinase and type I IFN receptor and unveils an intriguing proviral role of myeloid-specific IRF-3 expression during chronic gammaherpesvirus infection.IMPORTANCEThis study focuses on defining the mechanisms by which conserved gammaherpesvirus protein kinase facilitates establishment of chronic infection in vivo. We previously demonstrated that the viral protein kinase antagonizes STAT1 function in myeloid cells to allow gammaherpesvirus passage from myeloid cells to B cells in the spleen. Using a combination of virus and host genetics, this study demonstrates that the previously observed antagonism between viral protein kinase and STAT1 is at least in part due to antagonism of type I interferon (IFN) signaling. Despite the well-established role of IRF-3 in type I IFN expression, myeloid cell-specific IRF-3 deficiency failed to rescue attenuated chronic infection of viral kinase null gammaherpesvirus. Unexpectedly, splenic reactivation of wild-type gammaherpesvirus was decreased in mice with myeloid cell-specific IRF-3 deficiency, unveiling a proviral role of IRF-3 expressed by myeloid cells during chronic gammaherpesvirus infection.

PMID:
42678291
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.

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