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Altered host protease determinants for SARS-CoV-2 Omicron.

Jasper Fuk-Woo ChanXiner HuangBingjie HuYue ChaiHongyu ShiTianrenzheng ZhuTerrence Tsz-Tai YuenYuanchen LiuHuan LiuJialu ShiLei WenHuiping ShuaiYuxin HouChaemin YoonJian-Piao CaiAnna Jinxia ZhangJie ZhouFeifei YinShuo-Feng YuanBao-Zhong ZhangMelinda Ann BrindleyZheng-Li ShiKwok-Yung YuenHin Chu
Published in: Science advances (2023)
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.
Keyphrases
  • sars cov
  • respiratory syndrome coronavirus
  • angiotensin converting enzyme
  • coronavirus disease
  • small molecule
  • cell migration
  • genome wide
  • single cell
  • dna binding