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

Maritza Puray-Chavez, Jenna E. Eschbach, Ming Xia, Kyle M. LaPak, Qianzi Zhou, Ria Jasuja, Jiehong Pan, Jian Xu, Zixiang Zhou, Shawn Mohammed, Qibo Wang, Dana Q. Lawson, Sanja Djokic, Gaopeng Hou, Siyuan Ding, Steven L. Brody, Michael B. Major, Dennis Goldfarb and Sebla B. Kutluay ()
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Maritza Puray-Chavez: Washington University School of Medicine
Jenna E. Eschbach: Washington University School of Medicine
Ming Xia: Washington University School of Medicine
Kyle M. LaPak: Washington University School of Medicine
Qianzi Zhou: Washington University School of Medicine
Ria Jasuja: Washington University School of Medicine
Jiehong Pan: Washington University School of Medicine
Jian Xu: Washington University School of Medicine
Zixiang Zhou: Washington University School of Medicine
Shawn Mohammed: Washington University School of Medicine
Qibo Wang: Washington University School of Medicine
Dana Q. Lawson: Washington University School of Medicine
Sanja Djokic: Washington University School of Medicine
Gaopeng Hou: Washington University School of Medicine
Siyuan Ding: Washington University School of Medicine
Steven L. Brody: Washington University School of Medicine
Michael B. Major: Washington University School of Medicine
Dennis Goldfarb: Washington University School of Medicine
Sebla B. Kutluay: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52803-7

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