Murine Gammaherpesvirus 68 Has Evolved Gamma Interferon and Stat1-Repressible Promoters for the Lytic Switch Gene 50
Murine Gammaherpesvirus 68 Has Evolved Gamma Interferon and Stat1-Repressible Promoters for the Lytic Switch Gene 50
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DOI：
10.1128/jvi.02099-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Virgin, Herbert W.
中科院分区：
文献类型：
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作者：
Goodwin, Megan M.;Canny, Susan;Virgin, Herbert W.
细胞因子调节病毒基因表达，对病毒复制和发病有重要影响。γ干扰素（ifn - γ）是慢性小鼠γ疱疹病毒68 （γ HV68）感染的关键调节剂，也是γ HV68潜伏期再激活的有效抑制剂。巨噬细胞是对ifn - γ介导的γ HV68再激活控制有反应的细胞类型；然而，ifn - γ作用的分子机制尚不明确。在这里，我们报道ifn - γ抑制原代骨髓源性巨噬细胞中γ HV68的裂解复制，并降低必要的裂解开关基因50的转录水平。有趣的是，ifn - γ抑制两个已知基因50启动子的活性，表明炎症细胞因子可以直接调节γ HV68裂解开关基因的启动子。Stat1，而不是ifn - α / β信号，是ifn - γ作用所必需的。此外，Stat1缺失增加了基础γ HV68复制、基因50表达和启动子活性。总之，这些数据确定ifn - γ和Stat1是γ - HV68裂解周期的负调节因子，并提出了γ - HV68维持ifn - γ /Stat1应答基因50启动子以促进细胞外源控制裂解周期和潜伏周期之间交换的可能性。
Cytokines regulate viral gene expression with important consequences for viral replication and pathogenesis. Gamma interferon (IFN-gamma) is a key regulator of chronic murine gammaherpesvirus 68 (gamma HV68) infection and a potent inhibitor of gamma HV68 reactivation from latency. Macrophages are the cell type that is responsive to the IFN-gamma-mediated control of gamma HV68 reactivation; however, the molecular mechanism of this IFN-gamma action is undefined. Here we report that IFN-gamma inhibits lytic replication of gamma HV68 in primary bone marrow-derived macrophages and decreases transcript levels for the essential lytic switch gene 50. Interestingly, IFN-gamma suppresses the activity of the two known gene 50 promoters, demonstrating that an inflammatory cytokine can directly regulate the promoters for the gamma HV68 lytic switch gene. Stat1, but not IFN-alpha/beta signaling, is required for IFN-gamma action. Moreover, Stat1 deficiency increases basal gamma HV68 replication, gene 50 expression, and promoter activity. Together, these data identify IFN-gamma and Stat1 as being negative regulators of the gamma HV68 lytic cycle and raise the possibility that gamma HV68 maintains IFN-gamma/Stat1-responsive gene 50 promoters to facilitate cell-extrinsic control over the interchange between the lytic and latent cycles.