Asarnow Daniel, Wang Bei, Lee Wen-Hsin, Hu Yuanyu, Huang Ching-Wen, Faust Bryan, Ng Patricia Miang Lon, Ngoh Eve Zi Xian, Bohn Markus, Bulkley David, Pizzorno Andrés, Ary Beatrice, Tan Hwee Ching, Lee Chia Yin, Minhat Rabiatul Adawiyah, Terrier Olivier, Soh Mun Kuen, Teo Frannie Jiuyi, Yeap Yvonne Yee Chin, Seah Shirley Gek Kheng, Chan Conrad En Zuo, Connelly Emily, Young Nicholas J, Maurer-Stroh Sebastian, Renia Laurent, Hanson Brendon John, Rosa-Calatrava Manuel, Manglik Aashish, Cheng Yifan, Craik Charles S, Wang Cheng-I
Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.
Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore.
Cell. 2021 Jun 10;184(12):3192-3204.e16. doi: 10.1016/j.cell.2021.04.033. Epub 2021 Apr 24.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的感染是由病毒刺突蛋白与宿主受体血管紧张素转换酶2（ACE2）结合引发的，随后是病毒膜与宿主膜的融合。尽管阻断这种相互作用的抗体作为早期冠状病毒病2019（COVID-19）疗法正在紧急使用，但中和效力的确切决定因素仍然未知。我们发现了一系列能有效阻断ACE2结合但对活病毒表现出不同中和效力的抗体。令人惊讶的是，这些中和抗体可以抑制或增强刺突介导的膜融合以及多核巨细胞的形成，而多核巨细胞的形成与COVID-19患者的慢性组织损伤有关。冷冻电子显微镜显示，刺突-抗体复合物的多种结构具有不同的结合模式，不仅能阻断ACE2结合，还能改变由ACE2结合触发的刺突蛋白构象循环。我们表明，不同刺突构象的稳定导致刺突介导的膜融合的调节，这对COVID-19的病理学和免疫具有深远影响。
