2. Academic Validation
  3. Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity

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

  • Sci Adv. 2021 Jun 16;7(25):eabf8577. doi: 10.1126/sciadv.abf8577.
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

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 2 Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 3 Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 4 Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 5 Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 6 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 7 Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242, USA.
  • 8 State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. kyyuen@hku.hk jfwchan@hku.hk.
  • 9 Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China.
  • 10 Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
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.

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