RT Journal Article
SR Electronic
T1 SARS-CoV-2 Requires Cholesterol for Viral Entry and Pathological Syncytia Formation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.14.422737
DO 10.1101/2020.12.14.422737
A1 David W. Sanders
A1 Chanelle C. Jumper
A1 Paul J. Ackerman
A1 Dan Bracha
A1 Anita Donlic
A1 Hahn Kim
A1 Devin Kenney
A1 Ivan Castello-Serrano
A1 Saori Suzuki
A1 Tomokazu Tamura
A1 Alexander H. Tavares
A1 Mohsan Saeed
A1 Alex S. Holehouse
A1 Alexander Ploss
A1 Ilya Levental
A1 Florian Douam
A1 Robert F. Padera
A1 Bruce D. Levy
A1 Clifford P. Brangwynne
YR 2020
UL http://biorxiv.org/content/early/2020/12/14/2020.12.14.422737.abstract
AB 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 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.Cell-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 particlesCompeting Interest StatementC.P.B. is a scientific founder and consultant for Nereid Therapeutics. A.S.H. is a consultant for Dewpoint Therapeutics.