Research Article: Inhibition of murine herpesvirus-68 replication by IFN-gamma in macrophages is counteracted by the induction of SOCS1 expression

Date Published: August 3, 2018

Publisher: Public Library of Science

Author(s): Yong Shen, Saisai Wang, Fangfang Sun, Gang Zheng, Tingting Wu, Yushen Du, Suzhan Zhang, Jing Qian, Ren Sun, Laurie Tate Krug.

http://doi.org/10.1371/journal.ppat.1007202

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.

Partial Text

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]. Like all other herpesviruses, MHV-68 has two distinct life-cycle phases: lytic replication and latency. Intranasal infection of MHV-68 in laboratory mice results in a productive infection in lung epithelial cells and latency in B lymphocytes, dendritic cells, and macrophages [3–7]. 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 this report, we have shown that the IFN-γ-mediated inhibition of murine herpesvirus-68 replication is suppressed by TLR3-induced SOCS1 expression in macrophages. Specifically, MHV-68 induces the expression of SOCS1, a suppressor of cytokine signaling in the JAK-STAT1 pathway. This increased SOCS1 expression, induced by TLR3/ NF-κB signaling pathway, is functional in macrophages.

 

Source:

http://doi.org/10.1371/journal.ppat.1007202