SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination.
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.
Xiuwu Bian, Zhengrong Zhang, You Zheng, Zubiao Niu, Bo Zhang, Chenxi Wang, Xiaohong Yao, Haoran Peng, Del Nonno Franca, Yunyun Wang, Yichao Zhu, Yan Su, Meng Tang, Xiaoyi Jiang, He Ren, Meifang He, Yuqi Wang, Lihua Gao, Ping Zhao, Hanping Shi, Zhaolie Chen, Xiaoning Wang, Mauro Piacentini, Gerry Melino, Liang Liu, Hongyan Huang, Qiang Sun