SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation.

TitleSARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation.
Publication TypeJournal Article
Year of Publication2021
AuthorsSanders, DW, Jumper, CC, Ackerman, PJ, Bracha, D, Donlic, A, Kim, H, Kenney, D, Castello-Serrano, I, Suzuki, S, Tamura, T, Tavares, AH, Saeed, M, Holehouse, AS, Ploss, A, Levental, I, Douam, F, Padera, RF, Levy, BD, Brangwynne, CP
JournalElife
Volume10
Date Published2021 04 23
ISSN2050-084X
KeywordsA549 Cells, Angiotensin-Converting Enzyme 2, Cholesterol, Coculture Techniques, COVID-19, Giant Cells, Host-Pathogen Interactions, Humans, Lung, Membrane Fusion, Membrane Lipids, SARS-CoV-2, Virus Internalization
Abstract

<p>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.</p>

DOI10.7554/eLife.65962
Alternate JournalElife
PubMed ID33890572
PubMed Central IDPMC8104966
Grant ListPrinceton COVID-19 research funds / / Office of the Dean for Research, Princeton University /
Peter Paul Career Development Professorship / / Boston University /
R01 GM120351 / GM / NIGMS NIH HHS / United States
HL122531 / HL / NHLBI NIH HHS / United States
Research Fellowships for Young Scientists / / Japan Society for the Promotion of Science /
Award for Investigators in Pathogenesis / / Burroughs Wellcome Fund /
R01 HL122531 / HL / NHLBI NIH HHS / United States
Longer Life Foundation-RGA/Washington University Collaboration / / Longer Life Foundation /
Investigator lab / HHMI / Howard Hughes Medical Institute / United States
GM120351 / GM / NIGMS NIH HHS / United States
GM095467 / GM / NIGMS NIH HHS / United States
R35 GM134949 / GM / NIGMS NIH HHS / United States
Start-up fund / / Boston University /
Postdoctoral fellowship award / / Uehara Memorial Foundation /
P01 GM095467 / GM / NIGMS NIH HHS / United States
GM134949 / GM / NIGMS NIH HHS / United States
R01 GM124072 / GM / NIGMS NIH HHS / United States
GM124072 / GM / NIGMS NIH HHS / United States