Highly pathogenic coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)^1,2, Middle East respiratory syndrome coronavirus (MERS-CoV)³, and SARS-CoV-1⁴ vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture^5-7 and in patient tissues^8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that a cysteine-aspartic protease of the apoptosis cascade, caspase-6, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid (N) proteins, generating N fragments that serve as interferon (IFN) antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss of SARS-CoV-2-infected golden Syrian hamsters and improves the survival of mouse-adapted MERS-CoV (MERS-CoV_MA)-infected human DPP4 knock-in (hDPP4 KI) mice. Overall, our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.

包括严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) ^1,2、中东呼吸系统综合症冠状病毒 (MERS-CoV) ³和 SARS-CoV-1 4^在内的高致病性冠状病毒的传播性和致病性各不相同。然而，所有三种病毒的感染都会导致细胞培养物^5-7和患者组织^{8-10中的大量细胞凋亡}，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，我们表明细胞凋亡级联的半胱氨酸-天冬氨酸蛋白酶 caspase-6 是冠状病毒有效复制的重要宿主因子。我们证明 caspase-6 可切割冠状病毒核衣壳 (N) 蛋白，生成用作干扰素 (IFN) 拮抗剂的 N 片段，从而促进病毒复制。抑制 caspase-6 可显着减轻 SARS-CoV-2 感染的金色叙利亚仓鼠的肺部病理和体重减轻，并提高小鼠适应性 MERS-CoV (MERS-CoV MA) 感染的人 DPP4 敲入 (hDPP4)_的存活率KI) 小鼠。总的来说，我们的研究揭示了冠状病毒如何利用宿主细胞凋亡级联的一个组成部分来促进病毒复制。