Abstract
Human cytomegalovirus (HCMV) is a species-specific β-herpesvirus that infects for life up to 80% of the world’s population and causes severe morbidity in at-risk immunocompromised populations. Suppressors of cytokine signaling (SOCS)1 and SOCS3 are host proteins that act as inducible negative feedback regulators of cytokine signaling and have been implicated in several ocular diseases and viral infections. We recently found in our mouse model of experimental cytomegalovirus retinitis that subretinally-injected murine cytomegalovirus (MCMV) stimulates ocular SOCS1 and SOCS3 during retrovirus-induced immune suppression of murine AIDS (MAIDS), and that infiltrating macrophages are prominent cellular sources of retinal SOCS1 and SOCS3 expression. Herein we investigate possible virologic mechanisms whereby MCMV infection may stimulate SOCS1 and/or SOCS3 expression in cell culture. We report that infection of IC-21 mouse macrophages with MCMV propagated through the salivary glands of BALB/c mice, but not from tissue culture in C57BL/6 fibroblasts, transiently stimulates SOCS1 and SOCS3 mRNA transcripts, but not SOCS5 mRNA. Viral tegument proteins are insufficient for this stimulation, as replication-deficient UV-inactivated MCMV fails to stimulate SOCS1 or SOCS3 in IC-21 macrophages. By contrast, infection of murine embryonic fibroblasts (MEFs) with either productive MCMV or UV-inactivated MCMV significantly stimulates SOCS1 and SOCS3 mRNA expression early after infection. Treatment of MCMV-infected IC-21 mouse macrophages with the antiviral drug ganciclovir significantly decreases MCMV-stimulated SOCS3 expression at 3 days post-infection. These data suggest cell type-specific, different roles for viral immediate early or early gene expression and/or viral tegument proteins in the early stimulation of SOCS1 and SOCS3 during MCMV infection. Furthermore, putative biphasic stimulation of SOCS3 during late MCMV infection of IC-21 mouse macrophages may occur by divergent virologic mechanisms.
Highlights
80% of the world’s population is infected with human cytomegalovirus (HCMV) [1], a species-specific β-herpesvirus [2, 3] which remains latent in its host for life
Others have demonstrated that infection of bone marrow-derived macrophages with murine cytomegalovirus (MCMV) passaged through BALB/c-derived murine embryonic fibroblasts (MEFs) causes an increase in SOCS1 and SOCS3 mRNA expression levels from 2 to 24 hours after infection [41]
We found that SOCS1 (Fig 1A) and SOCS3 (Fig 1B), but not SOCS5 (Fig 1C), mRNA transcripts are up-regulated at early time points following infection of IC-21 monolayers with SGMCMV
Summary
80% of the world’s population is infected with human cytomegalovirus (HCMV) [1], a species-specific β-herpesvirus [2, 3] which remains latent in its host for life. Patients latently infected with HCMV who develop HIV/AIDS become susceptible to HCMV-related retinitis [5,6,7,8], and this remains the leading cause of blindness in AIDS patients not taking or resistant to combination antiretroviral therapy (cART) [9,10,11]. We study AIDS-related HCMV retinitis using a clinically relevant small animal model with retrovirus-induced immune suppression that mimics the symptoms and progression of AIDS in mice (MAIDS), eventually rendering them susceptible to experimental MCMV retinitis [18]. We previously found in this model that subretinallyinjected MCMV significantly stimulates intraocular suppressors of cytokine signaling (SOCS) and SOCS3 [19], host proteins that are inducible negative feedback regulators of cell signaling
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