State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, China.
Nature. 2022 Sep;609(7928):785-792. doi: 10.1038/s41586-022-05148-4. Epub 2022 Aug 3.
Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. ) (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-1 (ref. ), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture and in patient tissues, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.
高致病性冠状病毒，包括严重急性呼吸综合征冠状病毒 2（参考文献）（SARS-CoV-2）、中东呼吸综合征冠状病毒（MERS-CoV）和 SARS-CoV-1（参考文献），在其传染性和致病性方面有所不同。然而，这三种病毒的感染都会导致细胞培养物和患者组织中的大量细胞凋亡，这表明细胞凋亡与冠状病毒的发病机制之间存在潜在联系。在这里，我们表明，凋亡级联中的半胱氨酸天冬氨酸蛋白酶 caspase-6 是冠状病毒有效复制的重要宿主因素。我们证明 caspase-6 切割冠状病毒核衣壳蛋白，生成作为干扰素拮抗剂的片段，从而促进病毒复制。抑制 caspase-6 可显著减轻感染 SARS-CoV-2 的金黄地鼠的肺部病理和体重减轻，并提高感染经小鼠适应的 MERS-CoV 的表达人 DPP4 的小鼠的存活率。我们的研究揭示了冠状病毒如何利用宿主凋亡级联中的一个组成部分来促进病毒复制。
