Reversible Inhibition of Murine Cytomegalovirus Replication by Gamma Interferon (IFN-γ) in Primary Macrophages Involves a Primed Type I IFN-Signaling Subnetwork for Full Establishment of an Immediate-Early Antiviral State
Reversible Inhibition of Murine Cytomegalovirus Replication by Gamma Interferon (IFN-γ) in Primary Macrophages Involves a Primed Type I IFN-Signaling Subnetwork for Full Establishment of an Immediate-Early Antiviral State
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DOI：
10.1128/jvi.00373-11
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发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Ghazal, Peter
中科院分区：
文献类型：
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作者：
Kropp, Kai A.;Robertson, Kevin A.;Ghazal, Peter
活化的巨噬细胞在控制对感染的炎症反应中起核心作用，并被严格调节以快速启动对感染性攻击的反应。I型干扰素（α/β干扰素[IFN-α/β]）和II型干扰素（IFN-γ）在激活巨噬细胞和随后限制病毒感染方面起着至关重要的作用。这两种类型的干扰素信号通过相关但不同的信号通路，诱导大量的干扰素刺激的基因是重叠的，但可区分的。IFN，特别是IFN-γ，抑制DNA病毒如巨细胞病毒（CMV）的确切机制仍不完全清楚。在这里，我们调查的抗病毒状态，在巨噬细胞可逆抑制小鼠CMV IFN-γ。可逆抑制的分子分析的基础上，我们确定了一个显着的贡献与IFN-γ激活的限制性I型IFN子网。在干扰素-γ刺激的背景下，I型信号传导途径的基因敲除揭示了启动I型信号传导过程在巨噬细胞中形成完全不应状态的基本要求。在用IFN-γ活化巨噬细胞时，也可检测到IFN-β的最小瞬时诱导。在使用IFN-γ的剂量和动力学病毒复制抑制实验中，证明在感染的第一个小时内建立抗病毒作用。我们表明，在这些非常早期的抑制机制涉及阻断病毒的主要立即早期启动子活性。总之，我们的研究结果表明，引发I型IFN子网络有助于立即早期的抗病毒状态诱导的II型IFN激活的巨噬细胞，与潜在的进一步放大环促成瞬时诱导IFN-β。
Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-alpha/beta]) and type II interferon (IFN-gamma) play a crucial role in activating macrophages and subsequently restricting viral infections. Both types of IFNs signal through related but distinct signaling pathways, inducing a vast number of interferon-stimulated genes that are overlapping but distinguishable. The exact mechanism by which IFNs, particularly IFN-gamma, inhibit DNA viruses such as cytomegalovirus (CMV) is still not fully understood. Here, we investigate the antiviral state developed in macrophages upon reversible inhibition of murine CMV by IFN-gamma. On the basis of molecular profiling of the reversible inhibition, we identify a significant contribution of a restricted type I IFN subnetwork linked with IFN-gamma activation. Genetic knockout of the type I-signaling pathway, in the context of IFN-gamma stimulation, revealed an essential requirement for a primed type I-signaling process in developing a full refractory state in macrophages. A minimal transient induction of IFN-beta upon macrophage activation with IFN-gamma is also detectable. In dose and kinetic viral replication inhibition experiments with IFN-gamma, the establishment of an antiviral effect is demonstrated to occur within the first hours of infection. We show that the inhibitory mechanisms at these very early times involve a blockade of the viral major immediate-early promoter activity. Altogether our results show that a primed type I IFN subnetwork contributes to an immediate-early antiviral state induced by type II IFN activation of macrophages, with a potential further amplification loop contributed by transient induction of IFN-beta.