期刊
CELL DEATH AND DIFFERENTIATION
卷 28, 期 9, 页码 2765-2777出版社
SPRINGERNATURE
DOI: 10.1038/s41418-021-00782-3
关键词
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资金
- Key Science & Technology Project of Beijing Educational Committee
- Beijing Municipal Natural Science Foundation [KZ202110025029]
- Beijing Municipal Administration of Hospitals Incubating Program [PX2021033]
- National Key Research & Development Program of China [2018YFA0900804, 2019YFA0903801]
- National Natural Science Foundation of China [81872314, 31970685]
In COVID-19 patients, SARS-CoV-2 infection leads to the presence of heterotypic cell-in-cell structures in lung tissues with lymphocytes inside multinucleate syncytia. The membrane fusion induced by the spike glycoprotein is controlled by a bi-arginine motif, and candidate anti-viral drugs can efficiently inhibit this process. This study provides insights into the molecular and cellular mechanisms of SARS-CoV-2 pathogenesis and identifies potential novel targets for COVID-19 therapy.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (similar to 45.1 nm/s) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.
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