Coronavirus disease 2019 (COVID-19), the current pandemic disease, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I and III interferons (IFNs) are innate cytokines that are important in first-line defense against viruses. Like many other viruses, SARS-CoV-2 has evolved mechanisms to evade the antiviral effects of type I and III IFNs on multiple levels, including induction of IFN expression and cellular responses to IFNs.
In this review, we describe the innate detection mechanisms of SARS-CoV-2 and the mechanisms used by SARS-CoV-2 to evade type I and III IFN responses. We also discuss conflicting reports regarding impaired and robust type I IFN responses in severe Sars cov 2 interferon COVID-19 patients. Finally, we discuss how late but exaggerated IFN type I responses can exacerbate inflammation and contribute to the severe progression of COVID-19.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is spreading globally1,2. The World Health Organization has declared COVID-19 a pandemic and, as of December 20, 2020, more than 76 million confirmed cases and more than 1.6 million deaths have been reported worldwide. SARS-CoV-2 infection results in a wide spectrum of clinical manifestations, from asymptomatic or mild disease to severe disease3,4.
Although the death rate from COVID-19 is lower than that of the severe acute respiratory syndrome (SARS) caused by SARS-CoV and the Middle East respiratory syndrome (MERS) caused by MERS-CoV, it is much higher than the of influenza5,6. A better understanding of the immune responses against SARS-CoV-2 is needed to develop effective therapeutic strategies.
Interferons (IFNs) are powerful multifunctional cytokines secreted by various types of cells. In particular, type I and III IFNs play crucial roles in innate immune responses during viral infection. However, many viruses, including SARS-CoV-2, are known to inhibit type I and III IFN responses at various points, from cytokine production to receptor signaling. Furthermore, dysregulated IFN responses are associated with the immunopathogenesis of viral infection5.
In the current review, we describe the innate detection mechanisms of SARS-CoV-2 and the mechanisms of inhibition of SARS-CoV-2-mediated IFN responses. We also discuss the dysregulation of IFN responses in the context of hyper inflammation in COVID-19 patients. Finally, we propose a hypothesis about how late but exaggerated IFN type I responses may contribute to the severe progression of COVID-19.
IFN and signaling
Originally identified as secretory factors that inhibit viral infections, IFNs are classified into three groups: types I, II, and III. Type I IFNs consist of multiple IFN-α subtypes and a single IFN-β type, in addition to the less characterized IFN-δ, -ε, -κ, -τ, -ω, and -ζ. In contrast, the type II IFN cluster has only one member, IFN-γ, which is secreted by natural killer cells and T cells, but not directly by virus-infected cells, so it is not described in more detail in this review.
Type III IFNs are structurally related to the cytokines of the IL-10 family and consist of IFN-λ1 (IL-29), -λ2 (IL-28A), -λ3 (IL-28B) and -λ47,8, 9. IFN-β and IFN-λ can be secreted by any cell type after viral infection, whereas IFN-α is generally produced by immune cells, particularly monocytes and dendritic cells (DC).
Type I IFNs bind to the heterodimeric receptor complex of IFNAR1 and IFNAR2 and activate receptor-associated tyrosine kinases TYK2 and JAK1, which in turn phosphorylate STAT1 and STAT27,8,9. Together with IRF9, phosphorylated STAT1 and STAT2 form a trimeric complex called IFN-stimulated gene factor 3 (ISGF3) that subsequently enters the nucleus to bind to IFN-stimulated response elements (ISRE) and promote the transcription of hundreds of stimulated genes.
by IFN (ISG). ; Figure 1). A subset of ISG can also be up-regulated by unphosphorylated ISGF3, which is composed of high levels of unphosphorylated STAT1, unphosphorylated STAT2, and IRF910,11. Many ISGs directly suppress viral replication through various mechanisms, including inhibition of viral transcription/translation and degradation of viral nucleic acids. Activation of the IFN type I receptor can also promote homodimerization of STAT1, which binds to gamma-ray-activated (GAS) sequences and induces expression of the proinflamat gene.