Interferon antagonists encoded by SARS-CoV-2 at a glance

Abstract

The innate immune system is a powerful barrier against invading pathogens. Interferons (IFNs) are a major part of the cytokine-mediated anti-viral innate immune response. After recognition of a pathogen by immune sensors, signaling cascades are activated that culminate in the release of IFNs. These activate cells in an autocrine or paracrine fashion eventually setting cells in an anti-viral state via upregulation of hundreds of interferon-stimulated genes (ISGs). To evade the anti-viral effect of the IFN system, successful viruses like the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolved strategies to counteract both IFN induction and signaling. In fact, more than half of the about 30 proteins encoded by SARS-CoV-2 target the IFN system at multiple levels to escape IFN-mediated restriction. Here, we review recent insights into the molecular mechanisms used by SARS-CoV-2 proteins to suppress IFN production and the establishment of an anti-viral state.

Keywords: COVID-19; Immune evasion; Innate immunity; Interferon; SARS-CoV-2.

Fig. 1

Counteraction of the IFN system by SARS-CoV-2 proteins. Schematic depiction of the antagonism of the interferon (IFN) system by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins. Incoming or replicating virus is recognized by Toll-like receptors (TLRs) or RIG-I-like receptors (RLRs) which eventually activates interferon regulatory factor 3 (IRF3) either through TANK binding kinase protein 1 (TBK1) or via mitochondrial antiviral-signaling protein (MAVS). Activated IRF3 dimerizes and translocates to the nucleus, where it induces the production of IFNs. IFNs bind to their respective receptors (e.g., interferon alpha and beta receptor subunit 1, IFNAR) to induce janus kinase (JAK) and tyrosine kinase (TYK) mediated activation of signal transducer and activator of transcription (STATs). Activated STAT complexes (ISGF3) translocate to the nucleus, where they induce transcription of interferon-stimulated genes (ISGs). Induction of ISGs sets the cell in an antiviral state that restricts infection and replication of the virus. SARS-CoV-2 interferes with signal transduction at multiple levels, as indicated by red highlights. Nsp non-structural protein, N nucleocapsid protein, M matrix protein, ORF open reading frame