A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models

Puray-Chavez, M.; LaPak, K.; Jasuja, R.; Pan, J.; Xu, J.; Eschbach, J. E.; Mohammed, S.; Lawson, D.; Wang, Q.; Brody, S. L.; Major, M. B.; Goldfarb, D.; Kutluay, S. B.

doi:10.1101/2024.01.07.574522

bioRxiv · 10.1101/2024.01.07.574522

A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models

Puray-Chavez, M.·LaPak, K.·Jasuja, R.·Pan, J.·Xu, J.·Eschbach, J. E.·Mohammed, S.·Lawson, D.·Wang, Q.·Brody, S. L.·Major, M. B.·Goldfarb, D.·Kutluay, S. B.

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Abstract

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.

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Puray-Chavez, M., LaPak, K., Jasuja, R., Pan, J., Xu, J., Eschbach, J. E., Mohammed, S., Lawson, D., Wang, Q., Brody, S. L., Major, M. B., Goldfarb, D., Kutluay, S. B.. 2024-01-08. A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models. https://doi.org/10.1101/2024.01.07.574522

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