Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R–like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2– and SARS-CoV–induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2–inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.

高致病性冠状病毒感染导致大量细胞凋亡。然而，细胞凋亡在冠状病毒感染发病机制中的生理相关性尚不清楚。在这里，结合体外、离体和体内模型，我们证明了蛋白激酶 R 样内质网激酶 (PERK) 信号介导了中东呼吸综合征冠状病毒 (MERS-CoV) 感染的促凋亡信号。收敛于内在凋亡途径。抑制 PERK 信号传导或内在细胞凋亡都减轻了体内 MERS 发病机制。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 和 SARS-CoV 通过不同的机制诱导细胞凋亡，但抑制内在细胞凋亡同样限制了体外 SARS-CoV-2 和 SARS-CoV 诱导的细胞凋亡，并显着改善了肺损伤SARS-CoV-2 接种的人血管紧张素转换酶 2 (hACE2) 小鼠。总的来说，我们的研究提供了第一个证据，证明病毒诱导的细胞凋亡是高致病性冠状病毒的重要疾病决定因素，并表明该过程可以靶向减轻疾病的严重程度。