Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Biomedical Center, Zentrallabor für Proteinanalytik (Protein Analysis Unit), Medical Faculty, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Graduate School for Quantitative Biosciences (QBM), Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
Cell Rep. 2021 May 18;35(7):109126. doi: 10.1016/j.celrep.2021.109126. Epub 2021 Apr 27.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades most innate immune responses but may still be vulnerable to some. Here, we systematically analyze the impact of SARS-CoV-2 proteins on interferon (IFN) responses and autophagy. We show that SARS-CoV-2 proteins synergize to counteract anti-viral immune responses. For example, Nsp14 targets the type I IFN receptor for lysosomal degradation, ORF3a prevents fusion of autophagosomes and lysosomes, and ORF7a interferes with autophagosome acidification. Most activities are evolutionarily conserved. However, SARS-CoV-2 Nsp15 antagonizes IFN signaling less efficiently than the orthologs of closely related RaTG13-CoV and SARS-CoV-1. Overall, SARS-CoV-2 proteins counteract autophagy and type I IFN more efficiently than type II or III IFN signaling, and infection experiments confirm potent inhibition by IFN-γ and -λ1. Our results define the repertoire and selected mechanisms of SARS-CoV-2 innate immune antagonists but also reveal vulnerability to type II and III IFN that may help to develop safe and effective anti-viral approaches.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）逃避了大多数先天免疫反应，但仍可能容易受到一些反应的影响。在这里，我们系统地分析了 SARS-CoV-2 蛋白对干扰素（IFN）反应和自噬的影响。我们表明，SARS-CoV-2 蛋白协同作用以对抗抗病毒免疫反应。例如，Nsp14 靶向 I 型 IFN 受体进行溶酶体降解，ORF3a 阻止自噬体和溶酶体融合，而 ORF7a 干扰自噬体酸化。大多数活性在进化上是保守的。然而，SARS-CoV-2 Nsp15 拮抗 IFN 信号的效率不如密切相关的 RaTG13-CoV 和 SARS-CoV-1 的同源物。总的来说，SARS-CoV-2 蛋白对抗自噬和 I 型 IFN 的效率高于 II 型或 III 型 IFN 信号，感染实验证实 IFN-γ 和 -λ1 的强烈抑制作用。我们的研究结果定义了 SARS-CoV-2 先天免疫拮抗剂的作用谱和选择机制，但也揭示了对 II 型和 III 型 IFN 的易感性，这可能有助于开发安全有效的抗病毒方法。
