School of Life Sciences, Chongqing University, No.55 Daxuecheng South Road, Shapingba, Chongqing 401331, China; Institut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Straße 7, 14163 Berlin, Germany.
School of Life Sciences, Chongqing University, No.55 Daxuecheng South Road, Shapingba, Chongqing 401331, China.
Cell Host Microbe. 2023 Jul 12;31(7):1170-1184.e7. doi: 10.1016/j.chom.2023.06.002. Epub 2023 Jul 3.
The historically dominant SARS-CoV-2 Delta variant and the currently dominant Omicron variants carry a T492I substitution within the non-structural protein 4 (NSP4). Based on in silico analyses, we hypothesized that the T492I mutation increases viral transmissibility and adaptability, which we confirmed with competition experiments in hamster and human airway tissue culture models. Furthermore, we showed that the T492I mutation increases the replication capacity and infectiveness of the virus and improves its ability to evade host immune responses. Mechanistically, the T492I mutation increases the cleavage efficiency of the viral main protease NSP5 by enhancing enzyme-substrate binding, which increases production of nearly all non-structural proteins processed by NSP5. Importantly, the T492I mutation suppresses viral-RNA-associated chemokine production in monocytic macrophages, which may contribute to the attenuated pathogenicity of Omicron variants. Our results highlight the importance of NSP4 adaptation in the evolutionary dynamics of SARS-CoV-2.
历史上占主导地位的 SARS-CoV-2 德尔塔变体和目前占主导地位的奥密克戎变体在非结构蛋白 4（NSP4）内携带 T492I 取代。基于计算机模拟分析，我们假设 T492I 突变增加了病毒的传染性和适应性，我们在仓鼠和人呼吸道组织培养模型中的竞争实验中证实了这一点。此外，我们表明 T492I 突变增加了病毒的复制能力和感染力，并提高了其逃避宿主免疫反应的能力。从机制上讲，T492I 突变通过增强酶-底物结合来提高病毒主要蛋白酶 NSP5 的切割效率，从而增加了由 NSP5 加工的几乎所有非结构蛋白的产量。重要的是，T492I 突变抑制了单核巨噬细胞中病毒 RNA 相关趋化因子的产生，这可能导致奥密克戎变体的致病性减弱。我们的研究结果强调了 NSP4 适应在 SARS-CoV-2 进化动力学中的重要性。
