2. Academic Validation
  3. Altered host protease determinants for SARS-CoV-2 Omicron

Altered host protease determinants for SARS-CoV-2 Omicron

  • Sci Adv. 2023 Jan 20;9(3):eadd3867. doi: 10.1126/sciadv.add3867.
Jasper Fuk-Woo Chan 1 2 3 4 5 6,  Xiner Huang 1,  Bingjie Hu 1,  Yue Chai 1,  Hongyu Shi 7,  Tianrenzheng Zhu 1,  Terrence Tsz-Tai Yuen 1,  Yuanchen Liu 1,  Huan Liu 1,  Jialu Shi 1,  Lei Wen 1,  Huiping Shuai 1,  Yuxin Hou 1,  Chaemin Yoon 1,  Jian-Piao Cai 1,  Anna Jinxia Zhang 1 3,  Jie Zhou 1,  Feifei Yin 5 8,  Shuofeng Yuan 1 2 3,  Bao-Zhong Zhang 9,  Melinda A Brindley 10,  Zheng-Li Shi 11,  Kwok-Yung Yuen 1 2 3 4 5 6,  Hin Chu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology and Carol Yu Centre for Infection, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China.
  • 2 Department of Infectious Disease and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, People's Republic of China.
  • 3 Centre for Virology, Vaccinology, and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, People's Republic of China.
  • 4 Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong, Special Administrative Region, People's Republic of China.
  • 5 Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, Hainan Province, People's Republic of China; and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China.
  • 6 Guangzhou Laboratory, Guangdong Province, China.
  • 7 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, NY, New York, USA.
  • 8 Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan Province, China.
  • 9 CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, People's Republic of China.
  • 10 Department of Infectious Diseases and Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
  • 11 CAS Key Laboratory of Special Pathogens and Biosafety, Chinese Academy of Sciences, Wuhan Institute of Virology, Wuhan, Hubei, People's Republic of China.
PMID: 36662861 DOI: 10.1126/sciadv.add3867
Abstract

Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane Protease serine 2 in SARS-CoV-2 Infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting Enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine Protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional Protease determinants for SARS-CoV-2 Infection and enhance our understanding on the biology of coronavirus entry.

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