Abstract：
A weak production of INF-β along with an exacerbated release of pro-inflammatory cytokines have been reported during infection by the novel SARS-CoV-2 virus. SARS-CoV-2 encodes several proteins that are able to counteract the host immune system, which is believed to be one of the most important features contributing to the viral pathogenesis and development of a severe clinical outcomes. Previous reports demonstrated that the SARS-CoV-2 ORF6 protein strongly suppresses INF-β production by hindering the RIG-I, MDA-5, and MAVS signaling cascade. In the present study, we better characterized the mechanism by which the SARS-CoV-2 ORF6 counteracts IFN-β and interleukin-6 (IL-6), which plays a crucial role in the inflammation process associated with the viral infection. In the present study, we demonstrated that the SARS-CoV-2 ORF6 protein has evolved an alternative mechanism to guarantee host IFN-β and IL-6 suppression, in addition to the transcriptional control exerted on the genes. Indeed, a block in movement through the nucleopore of newly synthetized messenger RNA encoding the immune-modulatory cytokines IFN-β and IL-6 are reported here. The ORF6 accessory protein of SARS-CoV-2 displays a multifunctional activity and may represent one of the most important virulence factors. Where conventional antagonistic strategies of immune evasion-such as the suppression of specific transcription factors (e.g., IRF-3, STAT-1/2)-would not be sufficient, the SARS-CoV-2 ORF6 protein is the trump card for the virus, also blocking the movement of IFN-β and IL-6 mRNAs from nucleus to cytoplasm. Conversely, we showed that nuclear translocation of the NF-κB transcription factor is not affected by the ORF6 protein, although inhibition of its cytoplasmic activation occurred. Therefore, the ORF6 protein exerts a 360-degree inhibition of the antiviral response by blocking as many critical points as possible.
摘要：
已经报道了在新型SARS-CoV-2病毒感染期间INF-β的弱产生以及促炎细胞因子的加剧释放。SARS-CoV-2编码几种能够对抗宿主免疫系统的蛋白质，这被认为是导致病毒发病机制和严重临床结局发展的最重要特征之一。以前的报道表明，SARS-CoV-2ORF6蛋白通过阻碍RIG-I强烈抑制INF-β的产生，MDA-5和MAVS信号级联。在本研究中,我们更好地表征了SARS-CoV-2ORF6抵抗IFN-β和白介素-6（IL-6）的机制，在与病毒感染相关的炎症过程中起着至关重要的作用。在本研究中,我们证明了SARS-CoV-2ORF6蛋白已经进化出一种替代机制来保证宿主IFN-β和IL-6抑制，除了对基因的转录控制。的确,此处报道了编码免疫调节细胞因子IFN-β和IL-6的新合成的信使RNA通过核孔运动的阻滞。SARS-CoV-2的ORF6辅助蛋白具有多功能活性，可能是最重要的毒力因子之一。其中免疫逃避的常规拮抗策略-例如抑制特定转录因子(例如，IRF-3，STAT-1/2）-不够，SARS-CoV-2ORF6蛋白是病毒的王牌,还阻断IFN-β和IL-6mRNA从细胞核到细胞质的运动。相反，我们表明NF-κB转录因子的核易位不受ORF6蛋白的影响，尽管抑制了其细胞质激活。因此,ORF6蛋白通过阻断尽可能多的临界点来发挥对抗病毒反应的360度抑制作用。
