1. Academic Validation
  2. 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.
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.

Figures
Products