Frentzen Anne, Gürlevik Engin, Yuan Qinggong, Steinmann Eike, Ott Michael, Staeheli Peter, Schmid-Burgk Jonathan, Schmidt Tobias, Hornung Veit, Kuehnel Florian, Pietschmann Thomas
Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hanover, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hanover, Germany.
J Virol. 2015 Apr;89(7):3833-45. doi: 10.1128/JVI.03129-14. Epub 2015 Jan 21.
UNLABELLED: Hepatitis C virus (HCV) efficiently infects only humans and chimpanzees. Although the detailed mechanisms responsible for this narrow species tropism remain elusive, recent evidence has shown that murine innate immune responses efficiently suppress HCV replication. Therefore, poor adaptation of HCV to evade and/or counteract innate immune responses may prevent HCV replication in mice. The HCV NS3-4A protease cleaves human MAVS, a key cellular adaptor protein required for RIG-I-like receptor (RLR)-dependent innate immune signaling. However, it is unclear if HCV interferes with mouse MAVS function equally well. Moreover, MAVS-dependent signaling events that restrict HCV replication in mouse cells were incompletely defined. Thus, we quantified the ability of HCV NS3-4A to counteract mouse and human MAVS. HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signaling in human and mouse cells. Moreover, replicon-encoded protease cleaved a similar fraction of both MAVS variants. Finally, FLAG-tagged MAVS proteins repressed HCV replication to similar degrees. Depending on MAVS expression, HCV replication in mouse liver cells triggered not only type I but also type III IFNs, which cooperatively repressed HCV replication. Mouse liver cells lacking both type I and III IFN receptors were refractory to MAVS-dependent antiviral effects, indicating that the HCV-induced MAVS-dependent antiviral state depends on both type I and III IFN receptor signaling. IMPORTANCE: In this study, we found that HCV NS3-4A similarly diminished both human and mouse MAVS-dependent signaling in human and mouse cells. Therefore, it is unlikely that ineffective cleavage of mouse MAVS per se precludes HCV propagation in immunocompetent mouse liver cells. Hence, approaches to reinforce HCV replication in mouse liver cells (e.g., by expression of essential human replication cofactors) should not be thwarted by the poor ability of HCV to counteract MAVS-dependent antiviral signaling. In addition, we show that mouse MAVS induces both type I and type III IFNs, which together control HCV replication. Characterization of type I or type III-dependent interferon-stimulated genes in these cells should help to identify key murine restriction factors that preclude HCV propagation in immunocompetent mouse liver cells.
未标记：丙型肝炎病毒（HCV）仅能有效感染人类和黑猩猩。尽管导致这种狭窄物种嗜性的详细机制仍不清楚，但最近的证据表明，小鼠的先天免疫反应能有效抑制HCV复制。因此，HCV在逃避和/或对抗先天免疫反应方面的适应性较差，这可能会阻止HCV在小鼠体内复制。HCV NS3-4A蛋白酶可切割人MAVS，MAVS是RIG-I样受体（RLR）依赖性先天免疫信号传导所需的关键细胞衔接蛋白。然而，尚不清楚HCV是否同样能很好地干扰小鼠MAVS的功能。此外，在小鼠细胞中限制HCV复制的MAVS依赖性信号传导事件尚未完全明确。因此，我们量化了HCV NS3-4A对抗小鼠和人MAVS的能力。HCV NS3-4A在人和小鼠细胞中同样减弱了人和小鼠MAVS依赖性信号传导。此外，复制子编码的蛋白酶切割了相似比例的两种MAVS变体。最后，FLAG标签的MAVS蛋白对HCV复制的抑制程度相似。根据MAVS的表达情况，HCV在小鼠肝细胞中的复制不仅触发了I型干扰素，还触发了III型干扰素，二者协同抑制HCV复制。缺乏I型和III型干扰素受体的小鼠肝细胞对MAVS依赖性抗病毒效应不敏感，这表明HCV诱导的MAVS依赖性抗病毒状态依赖于I型和III型干扰素受体信号传导。 重要性：在本研究中，我们发现HCV NS3-4A在人和小鼠细胞中同样减弱了人和小鼠MAVS依赖性信号传导。因此，小鼠MAVS切割无效本身不太可能阻止HCV在具有免疫活性的小鼠肝细胞中传播。因此，增强HCV在小鼠肝细胞中复制的方法（例如，通过表达必需的人复制辅助因子）不应因HCV对抗MAVS依赖性抗病毒信号传导的能力差而受阻。此外，我们表明小鼠MAVS可诱导I型和III型干扰素，二者共同控制HCV复制。对这些细胞中I型或III型依赖性干扰素刺激基因的表征应有助于鉴定阻止HCV在具有免疫活性的小鼠肝细胞中传播的关键小鼠限制因子。
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