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Nat Commun
. 2024 Sep 27;15(1):8394.
doi: 10.1038/s41467-024-52803-7. A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models
Maritza Puray-Chavez 1 , Jenna E Eschbach 1 , Ming Xia 1 , Kyle M LaPak 2 , Qianzi Zhou 1 , Ria Jasuja 2 , Jiehong Pan 3 , Jian Xu 3 , Zixiang Zhou 1 , Shawn Mohammed 1 , Qibo Wang 1 , Dana Q Lawson 1 , Sanja Djokic 1 , Gaopeng Hou 1 , Siyuan Ding 1 , Steven L Brody 3 , Michael B Major 2 4 , Dennis Goldfarb 2 5 , Sebla B Kutluay 6
Affiliations
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.
. 2024 Sep 27;15(1):8394.
doi: 10.1038/s41467-024-52803-7. A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models
Maritza Puray-Chavez 1 , Jenna E Eschbach 1 , Ming Xia 1 , Kyle M LaPak 2 , Qianzi Zhou 1 , Ria Jasuja 2 , Jiehong Pan 3 , Jian Xu 3 , Zixiang Zhou 1 , Shawn Mohammed 1 , Qibo Wang 1 , Dana Q Lawson 1 , Sanja Djokic 1 , Gaopeng Hou 1 , Siyuan Ding 1 , Steven L Brody 3 , Michael B Major 2 4 , Dennis Goldfarb 2 5 , Sebla B Kutluay 6
Affiliations
- PMID: 39333139
- PMCID: PMC11437049
- DOI: 10.1038/s41467-024-52803-7
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.