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

[tetano]

Sci Adv


. 2021 Jun 16;7(25):eabf8577.
doi: 10.1126/sciadv.abf8577. Print 2021 Jun.
Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity


Hin Chu ^{1 2 3} , Huiping Shuai ^{1 2} , Yuxin Hou ² , Xi Zhang ² , Lei Wen ² , Xiner Huang ² , Bingjie Hu ² , Dong Yang ² , Yixin Wang ² , Chaemin Yoon ² , Bosco Ho-Yin Wong ² , Cun Li ² , Xiaoyu Zhao ² , Vincent Kwok-Man Poon ² , Jian-Piao Cai ² , Kenneth Kak-Yuen Wong ⁴ , Man-Lung Yeung ^{1 2 3} , Jie Zhou ^{1 2 3} , Rex Kwok-Him Au-Yeung ⁵ , Shuofeng Yuan ^{1 2 3} , Dong-Yan Jin ⁶ , Kin-Hang Kok ^{1 2} , Stanley Perlman ⁷ , Jasper Fuk-Woo Chan ^{8 2 3 9 10} , Kwok-Yung Yuen ^{8 2 3 9 10}



Affiliations

• PMID: 34134991
• DOI: 10.1126/sciadv.abf8577

Abstract

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.