tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Jenna E Eschbach[SUP] 1 [/SUP], Ming Xia[SUP] 1 [/SUP], Kyle M LaPak[SUP] 2 [/SUP], Qianzi Zhou[SUP] 1 [/SUP], Ria Jasuja[SUP] 2 [/SUP], Jiehong Pan[SUP] 3 [/SUP], Jian Xu[SUP] 3 [/SUP], Zixiang Zhou[SUP] 1 [/SUP], Shawn Mohammed[SUP] 1 [/SUP], Qibo Wang[SUP] 1 [/SUP], Dana Q Lawson[SUP] 1 [/SUP], Sanja Djokic[SUP] 1 [/SUP], Gaopeng Hou[SUP] 1 [/SUP], Siyuan Ding[SUP] 1 [/SUP], Steven L Brody[SUP] 3 [/SUP], Michael B Major[SUP] 2 4 [/SUP], Dennis Goldfarb[SUP] 2 5 [/SUP], Sebla B Kutluay[SUP] 6 [/SUP]
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[SUP] 1 [/SUP], Jenna E Eschbach[SUP] 1 [/SUP], Ming Xia[SUP] 1 [/SUP], Kyle M LaPak[SUP] 2 [/SUP], Qianzi Zhou[SUP] 1 [/SUP], Ria Jasuja[SUP] 2 [/SUP], Jiehong Pan[SUP] 3 [/SUP], Jian Xu[SUP] 3 [/SUP], Zixiang Zhou[SUP] 1 [/SUP], Shawn Mohammed[SUP] 1 [/SUP], Qibo Wang[SUP] 1 [/SUP], Dana Q Lawson[SUP] 1 [/SUP], Sanja Djokic[SUP] 1 [/SUP], Gaopeng Hou[SUP] 1 [/SUP], Siyuan Ding[SUP] 1 [/SUP], Steven L Brody[SUP] 3 [/SUP], Michael B Major[SUP] 2 4 [/SUP], Dennis Goldfarb[SUP] 2 5 [/SUP], Sebla B Kutluay[SUP] 6 [/SUP]
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.