Abstract
Gamma interferon (IFN-γ) is known to negatively regulate murine gammaherpesvirus-68 (MHV-68 or γHV-68) replication. This process involves the suppression of the viral gene replication and transcription activator (RTA) promoter, as well as activation of signal transducers and activators of transcription (STAT1). Notably, this effect is gradually attenuated during MHV-68 infection of bone marrow-derived macrophages (BMMs), which raised the possibility that the virus may utilize a mechanism that counteracts the antiviral effect of IFN-γ. By identifying the cellular factors that negatively regulate JAK-STAT1 signaling, we revealed that the infection of BMMs by MHV-68 induces the expression of suppressor of cytokine signaling 1 (SOCS1) and that depletion of SOCS1 restores the inhibitory effect of IFN-γ on virus replication. Moreover, we demonstrated that the expression of SOCS1 was induced as a result of the Toll-like receptor 3 (TLR3) mediated activation of the NF-κB signaling cascade. In conclusion, we report that TLR3-TRAF-NF-κB signaling pathway play a role in the induction of SOCS1 that counteracts the antiviral effect of IFN-γ during MHV-68 infection. This process is cell type-specific: it is functional in macrophages, but not in epithelial cells or fibroblasts. Our study reveals a mechanism that balances the immune responses and the escape of a gamma-herpesvirus in some antigen-presenting cells.
Highlights
Murine gamma-herpesvirus 68 (MHV-68 or γHV-68) naturally infects rodents and is genetically and biologically related to two human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) [1,2]
We show that MHV-68, a gamma-herpesvirus, is able to stimulate macrophages to produce the cellular protein suppressor of cytokine signaling 1 (SOCS1), which reduces the antiviral effect initiated by IFN-γ, in a cell type specific manner
We show that Toll-like receptor 3 (TLR3)-NF-κB signaling is responsible for the induced production of SOCS1
Summary
Murine gamma-herpesvirus 68 (MHV-68 or γHV-68) naturally infects rodents and is genetically and biologically related to two human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) [1,2]. MHV-68 has two distinct life-cycle phases: lytic replication and latency. The lytic replication of MHV-68 is characterized by the sequential expression of immediate-early, early, and late viral genes [8]. Replication and transcription activator (RTA) is an immediate-early gene product that is encoded primarily by open reading frame 50 (ORF50), which initiates the lytic gene expression program, and controls the switch from latency to lytic replication [9,10]. In bone marrow-derived macrophages (BMMs), IFN-γ can inhibit the promoters of the MHV-68 lytic switch gene RTA via the signal transducers and activators of transcription 1 (STAT1), resulting in reduced expression of RTA and inhibited viral lytic replication [7]. The inhibitory effect of IFN-γ/STAT1 on MHV-68 RTA expression is recognized as an antiviral mechanism
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