A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 Sep 2024
27 Sep 2024
Historique:
received:
07
01
2024
accepted:
22
09
2024
medline:
28
9
2024
pubmed:
28
9
2024
entrez:
27
9
2024
Statut:
epublish
Résumé
Host factors that define the cellular tropism of SARS-CoV-2 beyond the cognate ACE2 receptor are poorly defined. Here we report that SARS-CoV-2 replication is restricted at a post-entry step in a number of ACE2-positive airway-derived cell lines due to tonic activation of the cGAS-STING pathway mediated by mitochondrial DNA leakage and naturally occurring cGAS and STING variants. Genetic and pharmacological inhibition of the cGAS-STING and type I/III IFN pathways as well as ACE2 overexpression overcome these blocks. SARS-CoV-2 replication in STING knockout cell lines and primary airway cultures induces ISG expression but only in uninfected bystander cells, demonstrating efficient antagonism of the type I/III IFN-pathway in productively infected cells. Pharmacological inhibition of STING in primary airway cells enhances SARS-CoV-2 replication and reduces virus-induced innate immune activation. Together, our study highlights that tonic activation of the cGAS-STING and IFN pathways can impact SARS-CoV-2 cellular tropism in a manner dependent on ACE2 expression levels.
Identifiants
pubmed: 39333139
doi: 10.1038/s41467-024-52803-7
pii: 10.1038/s41467-024-52803-7
doi:
Substances chimiques
Nucleotidyltransferases
EC 2.7.7.-
Membrane Proteins
0
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
cGAS protein, human
EC 2.7.7.-
STING1 protein, human
0
ACE2 protein, human
EC 3.4.17.23
Interferons
9008-11-1
Interferon Type I
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8394Subventions
Organisme : Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)
ID : AI167695
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : T32CA009547-34
Informations de copyright
© 2024. The Author(s).
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