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Abstract
As a highly pathogenic human coronavirus, SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread. The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity. However, whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive. In this study, SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule (avSG) formation. Moreover, NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA, poly (I:C), inhibiting TBK1 and IRF3 phosphorylation, and restraining the nuclear translocalization of IRF3. Furthermore, HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection. Mechanistically, NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity. In contrast to the multiple targets of NSP5, the N protein specifically targeted cofactors upstream of RIG-I. The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I. Additionally, the N protein also affected the recognition of dsRNA by RIG-I. This study revealed the intimate correlation between SARS-CoV-2, the stress response, and innate antiviral immunity, shedding light on the pathogenic mechanism of COVID-19.
Highlights
Innate antiviral immunity plays an essential role in the initial detection and control of the spread of viral infection
We observed that the N and NSP5 proteins decreased the percentage of cells with SGs to less than 5% (Figs. 1a, b, f), exhibiting a more potent capability to counteract antiviral stress granule (avSG) formation than the other proteins, including structural and nonstructural proteins (Fig. 1a-e)
We found that SARS-CoV-2 encodes at least two proteins, N and NSP5, that regulate avSG formation resulting from plasmid transfection
Summary
Innate antiviral immunity plays an essential role in the initial detection and control of the spread of viral infection. Nucleic acids produced by viruses in infected cells can be recognized by the pattern recognition receptors (PRRs), leading to the activation of innate immune signaling cascades.[1] Viral nucleic acids including DNA and RNA are detected by distinct PRRs. Cyclic GMP-AMP synthase (cGAS) senses double-stranded DNA (dsDNA) and triggers the production of the second messenger cGAMP. CGAMP binds to the downstream endoplasmic reticulum (ER) adaptor molecule STING.[2] RIG-I–like receptors (RLRs), including RIG-I and MDA5, recognize viral dsRNA and activate the mitochondrial adaptor molecule MAVS.[3] The cGAS-STING and RIG-I/MDA5 signaling pathways converge on TBK1, the kinase for the transcription factor IRF3. Phosphorylation of IRF3 facilitates its dimerization and nuclear translocation to initiate transcription of type I and type III interferons (IFNs), which will activate the JAK-STAT pathway to induce the production of interferon-stimulated genes (ISGs) and establish an antiviral state.[1]
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