Dual Nature of Type I Interferons in SARS-CoV-2-Induced Inflammation

Abstract

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ability of our cells to secrete type I interferons (IFN-Is) is essential for the control of virus replication and for effective antiviral immune responses; for this reason, viruses have evolved the means to antagonize IFN-I. Inhibition of IFN-I production is pronounced in SARS-CoV-2 infection, which can impair the adaptive immune response and exacerbate inflammatory disease at late stages of infection. However, therapeutic boosting of IFN-I offers a narrow time window for efficacy and safety. Here, we discuss how limits placed on IFN-I by SARS-CoV-2 shape the immune response and whether this might be countered with therapeutic approaches and vaccine design.

Figure 1

Key Figure. Type-I Interferon (IFN-I), Adaptive Immunity, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) Infection. Schematic showing (A) the positive effect of IFN-I on activation of antigen-presenting dendritic cells (DCs) that interact with CD8⁺ T cells for differentiation of CD8⁺ cytotoxic T lymphocytes [that target and lyse virus-infected cells (shown as infected monocyte/macrophage)]. Similarly, IFN-I acts via DCs or directly on CD4⁺ T cells to promote the differentiation of T follicular helper (Tfh) cells that interact with B cells in germinal centers within secondary lymphoid organs for the production of affinity-matured antibody (Ab) that binds virus. (B) In the case of SARS-CoV-2 infection in mice and humans, IFN-I production is hindered, leading to poor T cell activation, reduced cytotoxic T lymphocyte (CTL) numbers, and reduced production of high affinity Abs that have undergone somatic hypermutation. This can lead to slower clearance of the virus and infected cells, and continued production of inflammatory mediators from infected (shown, is a monocyte/macrophage) and bystander cells. Abbreviations: IL, interleukin; PD-1, programmed death 1; TNF-α, tumor necrosis factor α.