The type I interferon (IFN) response is the major host arsenal against invading viruses. IRGM is a negative regulator of IFN responses under basal conditions. However, the role of human IRGM during viral infection has remained unclear. In this study, we show that IRGM expression is increased upon viral infection. IFN responses induced by viral PAMPs are negatively regulated by IRGM. Conversely, IRGM depletion results in a robust induction of key viral restriction factors including IFITMs, APOBECs, SAMHD1, tetherin, viperin, and HERC5/6. Additionally, antiviral processes such as MHC-I antigen presentation and stress granule signaling are enhanced in IRGM-deficient cells, indicating a robust cell-intrinsic antiviral immune state. Consistently, IRGM-depleted cells are resistant to the infection with seven viruses from five different families, including Togaviridae, Herpesviridae, Flaviviverdae, Rhabdoviridae, and Coronaviridae. Moreover, we show that Irgm1 knockout mice are highly resistant to chikungunya virus (CHIKV) infection. Altogether, our work highlights IRGM as a broad therapeutic target to promote defense against a large number of human viruses, including SARS-CoV-2, CHIKV, and Zika virus.

中文翻译：

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抑制 IRGM 建立强大的抗病毒免疫状态以限制致病病毒

I 型干扰素 (IFN) 反应是对抗入侵病毒的主要宿主武器。IRGM 是基础条件下 IFN 反应的负调节剂。然而，人类 IRGM 在病毒感染过程中的作用仍不清楚。在这项研究中，我们表明病毒感染后 IRGM 表达增加。病毒 PAMP 诱导的 IFN 反应受 IRGM 的负调控。相反，IRGM 耗竭导致关键病毒限制因子的强烈诱导，包括 IFITM、APOBEC、SAMHD1、tetherin、viperin 和 HERC5/6。此外，在 IRGM 缺陷细胞中，抗​​病毒过程（如 MHC-I 抗原呈递和应激颗粒信号传导）得到增强，表明存在强大的细胞内在抗病毒免疫状态。一致地，IRGM耗尽的细胞对来自五个不同家族的七种病毒的感染具有抵抗力，披膜病毒科、疱疹病毒科、黄病毒科、弹状病毒科和冠状病毒科。此外，我们表明Irgm1敲除小鼠对基孔肯雅病毒 (CHIKV) 感染具有高度抗性。总而言之，我们的工作强调 IRGM 作为一个广泛的治疗靶点，可以促进对大量人类病毒的防御，包括 SARS-CoV-2、CHIKV 和寨卡病毒。