TY - JOUR
T1 - Pharmacological activation of STING blocks SARS-CoV-2 infection
AU - Li, Minghua
AU - Ferretti, Max
AU - Ying, Baoling
AU - Descamps, Hélène
AU - Lee, Emily
AU - Dittmar, Mark
AU - Seung, Jaelee
AU - Whig, Kanupriya
AU - Kamalia, Brinda
AU - Dohnalová, Lenka
AU - Uhr, Giulia
AU - Zarkoob, Hoda
AU - Chen, Yu Chi
AU - Ramage, Holly
AU - Ferrer, Marc
AU - Lynch, Kristen
AU - Schultz, David C.
AU - Thaiss, Christoph A.
AU - Diamond, Michael S.
AU - Cherry, Sara
N1 - Publisher Copyright:
Copyright © 2021, American Association for the Advancement of Science.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106393239&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.abi9007
DO - 10.1126/sciimmunol.abi9007
M3 - Article
C2 - 34010142
AN - SCOPUS:85106393239
SN - 2470-9468
VL - 6
JO - Science immunology
JF - Science immunology
IS - 59
M1 - eabi9007
ER -