Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity

Chu, Hin; Shuai, Huiping; Hou, Yuxin; Zhang, Xi; Wen, Lei; Huang, Xiner; Hu, Bingjie; Yang, Dong; Wang, Yixin; Yoon, Chaemin; Wong, Bosco Ho-Yin; Li, Cun; Zhao, Xiaoyu; Poon, Vincent Kwok-Man; Cai, Jian-Piao; Wong, Kenneth Kak-Yuen; Yeung, Man-Lung; Zhou, Jie; Au-Yeung, Rex Kwok-Him; Yuan, Shuofeng; Jin, Dong-Yan; Kok, Kin-Hang; Perlman, Stanley; Chan, Jasper Fuk-Woo; Yuen, Kwok-Yung

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.