Significance of interferon-dependent antiviral response in coronavirus infection - from immunopathology to clinical relevance

Interferons (IFNs) play a key role in the antiviral immune response by activating IFN-stimulated genes (ISGs) that inhibit different steps of viral replication. There are three main types of IFNs: I (IFN-alpha, IFN-beta), II (IFN-gamma), and III (IFN-lambda), of which types I and III are key in the antiviral immune response. SARS-CoV-2, like other coronaviruses, has evolved mechanisms to evade the IFN response, which contributes to its pathogenesis and the severe course of COVID-19 disease. Recent studies have shown that patients with severe COVID-19 often have reduced levels of IFNs type I and III and the presence of autoantibodies against IFNs type I, which are associated with poorer clinical outcomes. Treatment trials for COVID-19 with IFNs have yielded mixed results, and meta-analyses have failed to confirm significant clinical benefits. Therefore, systemic IFN is not currently recommended for use in patients with COVID-19, both in mild and severe cases. This article reviews the mechanisms of IFN evasion by SARS-CoV-2, the variability in the clinical response to infection, and the current state of knowledge on IFN therapies for the treatment of COVID-19.