Abstract
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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a novel coronavirus that emerged in Wuhan, China in December 2019 [1]
Gene ontology (GO) enrichment analysis reveals that genes associated with IFN and antiviral defense are induced at the 48 hours time point (Fig. 1A and S1A)
We observed that SARS-CoV-2 induced type I IFNs, type III IFNs and interferon-stimulated genes (ISGs) expression in primary normal human bronchial epithelial (NHBE) cells at late time points post infection (Fig. 1J to L)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a novel coronavirus that emerged in Wuhan, China in December 2019 [1]. The development of effective antivirals is urgently needed for controlling SARS-CoV-2 infection and disease. As the first line of defense against infection, the host innate immune system within the respiratory tract recognizes viral pathogens by detecting their pathogen-associated molecular patterns (PAMPs) through host-encoded pattern recognition receptors (PRRs) [4]. Viral recognition by PRRs activates downstream signaling cascades, leading to the induction of effectors including type I and type III interferons (IFNs) [5]. IFNs subsequently bind to their specific receptors in an autocrine and paracrine manner to activate JAK/STAT signaling and up-regulate the expression of hundreds of interferon-stimulated genes (ISGs), conferring an antiviral state to the host cells. Activation of IFN and other innate immune pathways can potentially block infection. There are clinical trials underway to treat COVID-19 with IFNs with mixed success [6, 7]
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