Innate immunity and interferon in SARS-CoV-2 infection outcome

Abstract

Innate immunity and the actions of type I and III interferons (IFNs) are essential for protection from SARS-CoV-2 and COVID-19. Each is induced in response to infection and serves to restrict viral replication and spread while directing the polarization and modulation of the adaptive immune response. Owing to the distribution of their specific receptors, type I and III IFNs, respectively, impart systemic and local actions. Therapeutic IFN has been administered to combat COVID-19 but with differential outcomes when given early or late in infection. In this perspective, we sort out the role of innate immunity and complex actions of IFNs in the context of SARS-CoV-2 infection and COVID-19. We conclude that IFNs are a beneficial component of innate immunity that has mediated natural clearance of infection in over 700 million people. Therapeutic induction of innate immunity and use of IFN should be featured in strategies to treat acute SARS-CoV-2 infection in people at risk for severe COVID-19.

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.

Figure 2.

IFN actions against SARS-CoV-2 mediated by select ISGs. Cell infection progression of SARS-CoV-2 is depicted. In the context of IFN production or treatment type I and III IFNs signal through the Jak-STAT pathway and induce the assembly, nuclear accumulation, and activity of IFN-stimulated gene factor 3 (ISGF3) transcription factor that binds to the interferon-stimulated response element (ISRE) promoter region of ISGs, inducing their expression. Hundreds of ISGs, including OAS1, ISG15, MX1, are induced by IFNs. Major ISGs that suppress/restrict SARS-CoV-2 replication at specific steps in the viral life cycle are shown.