SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation.
ACE2
COVID-19
SARS-CoV-2
cell biology
coronavirus
human
spike
syncytia
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
23 04 2021
23 04 2021
Historique:
received:
21
12
2020
accepted:
01
04
2021
pubmed:
24
4
2021
medline:
14
5
2021
entrez:
23
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33890572
doi: 10.7554/eLife.65962
pii: 65962
pmc: PMC8104966
doi:
pii:
Substances chimiques
Membrane Lipids
0
Cholesterol
97C5T2UQ7J
ACE2 protein, human
EC 3.4.17.23
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : GM134949
Pays : United States
Organisme : NHLBI NIH HHS
ID : HL122531
Pays : United States
Organisme : Howard Hughes Medical Institute
ID : Investigator lab
Pays : United States
Organisme : NIGMS NIH HHS
ID : GM120351
Pays : United States
Organisme : NIGMS NIH HHS
ID : GM095467
Pays : United States
Organisme : NIGMS NIH HHS
ID : GM124072
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134949
Pays : United States
Organisme : NIAID NIH HHS
ID : U24 AI118656
Pays : United States
Informations de copyright
© 2021, Sanders et al.
Déclaration de conflit d'intérêts
DS, CJ, PA, DB, AD, HK, DK, IC, SS, TT, AT, MS, AP, IL, FD, RP, BL No competing interests declared, AH ASH is a consultant for Dewpoint Therapeutics. CB CPB is a scientific founder and consultant for Nereid Therapeutics.
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