SARS-CoV-2 entry into human airway organoids is serine protease-mediated and facilitated by the multibasic cleavage site

eLife

Robbert J Rottier¹  Bart L Haagmans²  Tim I Breugem²  Petra B van den Doel²  Samra Riesebosch²  Anna Z Mykytyn²  Mart M Lamers²  Debby Schipper² 

[1] Department of Pediatric Surgery, Erasmus University Medical Center - Sophia Children's Hospital, Rotterdam, Netherlands;Viroscience Department, Erasmus University Medical Center, Rotterdam, Netherlands;

关键词: COVID-19;    SARS-CoV-2;    SARS-CoV;    multibasic cleavage site;    serine proteases;    airway organoids;   

DOI  :  10.7554/eLife.64508

来源: DOAJ

【 摘 要 】

Coronavirus entry is mediated by the spike protein that binds the receptor and mediates fusion after cleavage by host proteases. The proteases that mediate entry differ between cell lines, and it is currently unclear which proteases are relevant in vivo. A remarkable feature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the presence of a multibasic cleavage site (MBCS), which is absent in the SARS-CoV spike. Here, we report that the SARS-CoV-2 spike MBCS increases infectivity on human airway organoids (hAOs). Compared with SARS-CoV, SARS-CoV-2 entered faster into Calu-3 cells and, more frequently, formed syncytia in hAOs. Moreover, the MBCS increased entry speed and plasma membrane serine protease usage relative to cathepsin-mediated endosomal entry. Blocking serine proteases, but not cathepsins, effectively inhibited SARS-CoV-2 entry and replication in hAOs. Our findings demonstrate that SARS-CoV-2 enters relevant airway cells using serine proteases, and suggest that the MBCS is an adaptation to this viral entry strategy.

【 授权许可】

Unknown