Abstract
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 (~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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Acknowledgements
We thank Dr. Cheng Cao, Dr. Hui Zhong and Dr. Guan Yang at Beijing Institute of Biotechnology for reagents. Dr. Hongguang Ren and Dr. Junjie Yue at Beijing Institute of Biotechnology for assistance in bioinformatics.
Funding
This work was supported by the Key Science & Technology Project of Beijing Educational Committee and the Beijing Municipal Natural Science Foundation (KZ202110025029 to HH), Beijing Municipal Administration of Hospitals Incubating Program (PX2021033 to HH), the National Key Research & Development Program of China (2018YFA0900804 to YZ and ZC, 2019YFA0903801 to QS), and the National Natural Science Foundation of China (81872314 to ZC, 31970685 to QS).
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Contributions
Concept and design: QS; Phenotype: QS and ZZ; Tissue staining, imaging and analysis: ZN and YQW; Human specimen and sections: XY, XB, DF, MP, YYW and LL; Virus induced fusion: HP and PZ; S protein induced fusion and imaging: ZZ and ZN; Cell-in-cell experiments: YZ, YS, YCZ, MH; Gene cloning: BZ; Expression detection: CW; Data analysis: YCZ, MT, WG, XJ, HR, LG; Bioinformatics: QS; Figures: QS, HH and YCZ; Data interpretation: QS, HH; Manuscript: QS, GM, HH, XW, HS; Funding: QS, HH, YZ and ZC. All authors have read and approved the final manuscript.
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Ethics statement
The autopsy for COVID-19 death was carried out with informed consent under the approval of Ethics Committee of Wuhan Infectious Diseases Hospital (KY-2020-15.01) and Ethics Committee of the First Affiliated Hospital of Army Medical University (KY2020298).
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41418_2021_782_MOESM4_ESM.tif (download TIF )
Fig. S4 Subtyping T lymphocytes internalized into syncytia, and effects of candidate compounds on CIC formation. Related to Figure 3.
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Zhang, Z., Zheng, Y., Niu, Z. et al. SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination. Cell Death Differ 28, 2765–2777 (2021). https://doi.org/10.1038/s41418-021-00782-3
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DOI: https://doi.org/10.1038/s41418-021-00782-3
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