Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 59, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abi9007
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Funding
- National Institutes of Health [R01AI074951, R01AI122749, 1R21AI151882, R01AI140539]
- Penn Center for Precision Medicine, Mercatus
- Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award
- Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health [TR00041401]
- Gates Foundation
- [T32 AI055400]
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The study reveals that SARS-CoV-2 evades interferon activation in respiratory epithelial cells, but pharmacological activation of innate immune pathways can effectively control the viral infection. Using STING activation as a potential therapeutic strategy, the small molecule STING agonist diABZI inhibits viral replication by stimulating IFN signaling.
Severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B. 1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS- CoV-2.
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