Abstract
SARS-CoV-2 cell-cell fusion and syncytiation is an emerging pathomechanism in COVID-19, but the precise factors contributing to the process remain ill-defined. In this study, we show that metalloproteases promote SARS-CoV-2 spike protein-induced syncytiation in the absence of established serine proteases using in vitro cell-cell fusion assays. We also show that metalloproteases promote S2′-activation of the SARS-CoV-2 spike protein, and that metalloprotease inhibition significantly reduces the syncytiation of SARS-CoV-2 variants of concern. In the presence of serine proteases, however, metalloprotease inhibition does not reduce spike protein-induced syncytiation and a combination of metalloprotease and serine protease inhibition is necessitated. Moreover, we show that the spike protein induces metalloprotease-dependent ectodomain shedding of the ACE2 receptor and that ACE2 shedding contributes to spike protein-induced syncytiation. These observations suggest a benefit to the incorporation of pharmacological inhibitors of metalloproteases into treatment strategies for patients with COVID-19.
Keywords: ACE2; SARS-CoV-2; SARS-CoV-2 spike protein; metalloproteases; syncytiation.
【저자키워드】 SARS-CoV-2, ACE2, SARS-CoV-2 spike protein, metalloproteases, syncytiation., 【초록키워드】 COVID-19, SARS-CoV-2 variant, ACE2 receptor, in vitro, Spike protein, cell-cell fusion, inhibitor, SARS-CoV-2 spike, Combination, treatment strategy, observation, Factor, serine protease, ectodomain, pharmacological, serine proteases, benefit, significantly, assays, contribute, absence, the spike protein, promote, induce, contributing to, reduce, not reduce, patients with COVID-19, the SARS-CoV-2, 【제목키워드】 fusion,