Alston Christine I, Dix Richard D
Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
PLoS One. 2017 Feb 9;12(2):e0171812. doi: 10.1371/journal.pone.0171812. eCollection 2017.
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.
人巨细胞病毒（HCMV）是一种种属特异性的β疱疹病毒，全球高达80%的人口会终身感染该病毒，并且在免疫功能低下的高危人群中会引发严重疾病。细胞因子信号转导抑制因子（SOCS）1和SOCS3是宿主蛋白，作为细胞因子信号转导的诱导性负反馈调节因子，与多种眼部疾病和病毒感染有关。我们最近在实验性巨细胞病毒性视网膜炎的小鼠模型中发现，视网膜下注射鼠巨细胞病毒（MCMV）在逆转录病毒诱导的小鼠获得性免疫缺陷综合征（MAIDS）免疫抑制期间刺激眼部SOCS1和SOCS3，并且浸润的巨噬细胞是视网膜SOCS1和SOCS3表达的主要细胞来源。在此，我们研究MCMV感染在细胞培养中刺激SOCS1和/或SOCS3表达的可能病毒学机制。我们报告，用通过BALB/c小鼠唾液腺繁殖的MCMV感染IC-21小鼠巨噬细胞，而不是用C57BL/6成纤维细胞中的组织培养物感染，会短暂刺激SOCS1和SOCS3 mRNA转录本，但不会刺激SOCS5 mRNA。病毒被膜蛋白不足以产生这种刺激，因为复制缺陷的紫外线灭活MCMV无法刺激IC-21巨噬细胞中的SOCS1或SOCS3。相比之下，用有活性的MCMV或紫外线灭活的MCMV感染鼠胚胎成纤维细胞（MEF）在感染后早期会显著刺激SOCS1和SOCS3 mRNA表达。用抗病毒药物更昔洛韦处理MCMV感染的IC-21小鼠巨噬细胞，在感染后3天会显著降低MCMV刺激的SOCS3表达。这些数据表明，在MCMV感染期间，病毒即刻早期或早期基因表达和/或病毒被膜蛋白在早期刺激SOCS1和SOCS3方面具有细胞类型特异性的不同作用。此外，在IC-21小鼠巨噬细胞的MCMV晚期感染期间，SOCS3可能通过不同的病毒学机制出现假定的双相刺激。
