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