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
  • 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. [email protected] [email protected].
  • 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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