| Autor: |
Puray-Chavez, Maritza, Eschbach, Jenna E., Xia, Ming, LaPak, Kyle M., Zhou, Qianzi, Jasuja, Ria, Pan, Jiehong, Xu, Jian, Zhou, Zixiang, Mohammed, Shawn, Wang, Qibo, Lawson, Dana Q., Djokic, Sanja, Hou, Gaopeng, Ding, Siyuan, Brody, Steven L., Major, Michael B., Goldfarb, Dennis, Kutluay, Sebla B. |
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| Zdroj: |
Nature Communications; 9/27/2024, Vol. 15 Issue 1, p1-20, 20p |
| Abstrakt: |
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. Factors that determine the cellular tropism of SARS-CoV-2 beyond the host cell receptor, ACE2, are poorly defined. Here, the authors show that tonic activation of the cGAS-STING sensing pathway potently blocks SARS-CoV-2 replication in a subset of ACE2-expressing airway-derived cells. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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