Author:
Sanders David W.,Jumper Chanelle C.,Ackerman Paul J.,Bracha Dan,Donlic Anita,Kim Hahn,Kenney Devin,Castello-Serrano Ivan,Suzuki Saori,Tamura Tomokazu,Tavares Alexander H.,Saeed Mohsan,Holehouse Alex S.,Ploss Alexander,Levental Ilya,Douam Florian,Padera Robert F.,Levy Bruce D.,Brangwynne Clifford P.
Abstract
SummaryMany 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 cell biological and biophysical approaches, the screen reveals an essential role for membrane cholesterol in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings 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.HighlightsCell-cell fusion at ACE2-spike clusters cause pathological syncytia in COVID-19Drug screen reveals critical role for membrane lipid composition in fusionSpike’s unusual membrane-proximal cysteines and aromatics are essential for fusionCholesterol tunes relative infectivity of SARS-CoV-2 viral particles
Publisher
Cold Spring Harbor Laboratory
Cited by
11 articles.
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