Martiáñez-Vendrell Xavier, van Kasteren Puck B, Myeni Sebenzile K, Kikkert Marjolein
Molecular Virology Laboratory, Leiden University Center of Infectious Diseases (LU-CID), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Int J Mol Sci. 2025 Jan 30;26(3):1197. doi: 10.3390/ijms26031197.
In order to detect and respond to invading pathogens, mammals have evolved a battery of pattern recognition receptors. Among these, RIG-I-like receptors (RLR) are cytosolic RNA sensors that play an essential role in the innate immune response against RNA viruses, including coronaviruses. In return, coronaviruses have acquired diverse strategies to impair RLR-mediated immune responses to enable productive infection. Viral innate immune evasion mechanisms have been well studied for highly pathogenic human coronaviruses (HCoVs), and often, these activities are thought to be linked to the severe symptoms these viruses can cause. Whether other coronaviruses, including human common cold coronaviruses, display similar activities has remained understudied. Here, we present evidence that the main protease (Mpro) of common cold HCoV-229E acts as an interferon (IFN) and NF-κB antagonist by disrupting RLR-mediated antiviral signalling. Furthermore, we show that HCoV-229E, HCoV-OC43 and MERS-CoV Mpros are able to directly cleave NEMO. We also show that HCoV-229E Mpro induces the cleavage and/or degradation of multiple other RLR pathway components, including MDA5, TBK1 and IKKε. Finally, we show that HCoV-229E infection leads to a delayed innate immune response that is accompanied by a decrease in NEMO protein levels. Our results suggest that NEMO degradation during HCoV-229E infection could be mediated, in part, by cellular degradation pathways, in addition to viral Mpro-mediated cleavage. Altogether, our research unveils innate immune evasion activities of the Mpros of low-pathogenic coronaviruses, which, despite their low pathogenicity, appear to share functionalities previously described for highly pathogenic HCoVs.
为了检测并应对入侵的病原体，哺乳动物进化出了一系列模式识别受体。其中，维甲酸诱导基因I样受体（RLR）是胞质RNA传感器，在针对包括冠状病毒在内的RNA病毒的先天免疫反应中发挥着至关重要的作用。作为回应，冠状病毒已获得多种策略来损害RLR介导的免疫反应，以实现有效感染。对于高致病性人类冠状病毒（HCoV），病毒先天免疫逃逸机制已得到充分研究，而且通常认为这些活性与这些病毒可能导致的严重症状有关。包括人类普通感冒冠状病毒在内的其他冠状病毒是否表现出类似活性仍未得到充分研究。在此，我们提供证据表明，普通感冒HCoV - 229E的主要蛋白酶（Mpro）通过破坏RLR介导的抗病毒信号传导，充当干扰素（IFN）和核因子κB拮抗剂。此外，我们表明HCoV - 229E、HCoV - OC43和中东呼吸综合征冠状病毒（MERS-CoV）的Mpro能够直接切割NEMO。我们还表明，HCoV - 229E的Mpro诱导包括黑色素瘤分化相关基因5（MDA-5）、TANK结合激酶1（TBK1）和IκB激酶ε（IKKε）在内的多种其他RLR途径成分的切割和/或降解。最后，我们表明HCoV - 229E感染导致先天免疫反应延迟，同时伴有NEMO蛋白水平降低。我们的结果表明，HCoV - 229E感染期间NEMO的降解可能部分由细胞降解途径介导，此外还有病毒Mpro介导的切割。总之，我们的研究揭示了低致病性冠状病毒Mpro的先天免疫逃逸活性，尽管它们致病性较低，但似乎具有先前描述的高致病性HCoV的功能。
