COVID-19 is a current global health threat caused by the novel coronavirus SARS-CoV-2. Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferons (IFNs) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated.
In this paper, it’s reported the activation and repression of innate immune response by SARS-CoV-2.
It’s shown that:
- SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway.
- ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells.
- ORF9b targets the NF-κB essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IKKα/β/γ-NF-κB signaling and subsequent IFN production.
Our findings thus unveil the innate immunosuppression by ORF9b, and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection.