Department of Chemical and Biological Engineering, Princeton University, Princeton, United States
Chanelle C Jumper
Department of Chemical and Biological Engineering, Princeton University, Princeton, United States
Paul J Ackerman
Department of Chemical and Biological Engineering, Princeton University, Princeton, United States
Dan Bracha
Department of Chemical and Biological Engineering, Princeton University, Princeton, United States
Anita Donlic
Department of Chemical and Biological Engineering, Princeton University, Princeton, United States
Hahn Kim
Princeton University Small Molecule Screening Center, Princeton University, Princeton, United States; Department of Chemistry, Princeton University, Princeton, United States
Devin Kenney
Department of Microbiology, Boston University School of Medicine, Boston, United States; National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States
Ivan Castello-Serrano
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
Department of Molecular Biology, Princeton University, Princeton, United States
Alexander H Tavares
National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States; Department of Biochemistry, Boston University School of Medicine, Boston, United States
Mohsan Saeed
National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States; Department of Biochemistry, Boston University School of Medicine, Boston, United States
Department of Molecular Biology, Princeton University, Princeton, United States
Ilya Levental
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, United States
Florian Douam
Department of Microbiology, Boston University School of Medicine, Boston, United States; National Emerging Infectious Diseases Laboratories, Boston University, Boston, United States
Robert F Padera
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States
Bruce D Levy
Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States
Department of Chemical and Biological Engineering, Princeton University, Princeton, United States; Howard Hughes Medical Institute, Princeton, United States
Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.
