Figure 1.

SARS-CoV-2 induction of innate immune activation and IFNs. SAR-CoV-2 infection and cell entry results in viral RNA deposition in the cell cytosol to initiate viral protein synthesis and viral RNA replication. Left: MDA5 first senses viral products, likely viral RNA components, and undergoes signaling activation involving interaction with the MAVS adaptor protein. SARS-CoV-2 might also be sensed through other pathogen recognition receptors including specific Toll-like receptors. Signaling mediates downstream activation and nuclear accumulation of IRF3, NF-KB, and other transcription factors that direct the expression of virus-stimulated genes (VSGs), many with antiviral and immune-modulatory activity. Right: Type I and III IFNs are cytokine VSG products and are secreted from the infected cell and signal via distinct receptors engaging the Jak-STAT pathway leading to interferon stimulated gene (ISG) expression. Hundreds of ISGs are induced in lung epithelial cells. ISG actions amplify and diversify the innate immune response, with the responses to type I and type III IFNs being temporally distinct and respectively partitioned by systemic versus compartmentalized (type III IFN) receptor expression distribution. Specific ISGs mediate antiviral actions against SARS-CoV-2. IFN therapy strategies leverage these actions and the immunomodulatory activities of ISGs for the treatment of infection and COVID-19.