A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models
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.
Authors
- Michael B. Major (ORCID: https://orcid.org/0000-0002-6753-8513)
- Qianzi Zhou
- Gaopeng Hou (ORCID: https://orcid.org/0000-0003-4753-9743)
- Siyuan Ding (ORCID: https://orcid.org/0000-0002-5338-260X)
- Dana Q. Lawson (ORCID: https://orcid.org/0000-0002-9625-398X)
- Kyle M. LaPak (ORCID: https://orcid.org/0000-0002-7571-4222)
- Dennis Goldfarb (ORCID: https://orcid.org/0000-0002-1584-5423)
- Steven L. Brody (ORCID: https://orcid.org/0000-0002-0905-7527)
- Jiehong Pan (ORCID: https://orcid.org/0000-0003-2384-6845)
- Sebla B. Kutluay (ORCID: https://orcid.org/0000-0001-5549-7032)
- Sanja Djokic
- Maritza Puray‐Chavez (ORCID: https://orcid.org/0000-0002-7983-0757)
- Ria Jasuja (ORCID: https://orcid.org/0000-0002-2984-4827)
- Jian Xu (ORCID: https://orcid.org/0000-0003-4050-0168)
- Qibo Wang (ORCID: https://orcid.org/0009-0003-3337-0833)
- Ming Xia (ORCID: https://orcid.org/0000-0001-8267-6263)
- Zixiang Zhou
- Jenna E. Eschbach (ORCID: https://orcid.org/0000-0001-9107-4504)
- Shawn Mohammed (ORCID: https://orcid.org/0000-0002-5189-3713)
Institutions
- Washington University in St. Louis (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41467-024-52803-7
- Citations
- 8
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 1.92
Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Cancer Institute