Type I Interferons in COVID-19 Pathogenesis

Abstract

Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Viruses likewise have evolved multiple immune evasion strategies to circumvent the host immune response and promote virus propagation and dissemination. Therefore, a thorough characterization of host-virus interactions is essential to understand SARS-CoV-2 pathogenesis. Here, we summarize the virus-mediated evasion of the IFN responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.

Keywords: COVID-19; SARS-CoV-2; innate immunity; type I IFNs.

Figure 1

Schematic representation of SARS-CoV-2 genomic organization and gene products. Red arrows, pointed at genes, represent the inhibition of IFN-I production and response determined by the corresponding SARS-CoV-2 gene product. Blue arrows, pointed at genes, represent the inhibition of IFN-I production and response determined by the corresponding SARS-CoV gene product. Combined red and blue arrows, pointed at ORF-6 and NSP1, represent the inhibition of the IFN-I production and the response to IFN-I, determined by the corresponding SARS-CoV and SARS-CoV-2 gene products. * = increased anti-IFN activity in its naturally occurring elongation variant.

Figure 2

Schematic overview of type I IFN production and response and the counter measures due to the activity of several SARS-CoV-2 (red) and SARS-CoV (blue) proteins. These factors act at different steps in the signal transduction pathway, leading to inhibition of IFN-I production in the first stage and, subsequently, by inactivating the JAK–STAT–ISGF3 pathway, impairing ISGs transcription. ORF6 and Nsp1 represent the main inhibitors of IFN production and signaling (emphasized in green).