Type I and Type III Interferons - Induction, Signaling, Evasion, and Application to Combat COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Without approved antiviral therapeutics or vaccines to this ongoing global threat, type I and type III interferons (IFNs) are currently being evaluated for their efficacy. Both the role of IFNs and the use of recombinant IFNs in two related, highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, have been controversial in terms of their protective effects in the host. In this review, we describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy for COVID-19.

Figure 1

Innate Recognition, Interferon Signaling, and Immune Evasion by Coronaviruses Upon sensing of coronaviruses by various pathogen recognition receptors, TLRs (TLR3, TLR4, TLR7, TLR8; blue) and RLRs (RIG-I, MDA5; purple), transcription factors nuclear factor-κΒ (NF-κB) and interferon regulatory factor 3 and 7 (IRF3, IRF7) stimulate the production of pro-inflammatory cytokines and type I and III interferons (IFNs), respectively. IFNs are secreted in an autocrine and paracrine manner to induce expression of interferon-stimulated genes (ISGs) via the JAK-STAT signaling pathway. While type I and III IFNs induce a similar set of ISGs, type I IFN signaling activates a stronger and faster ISG response, in addition to expression of pro-inflammatory cytokines and chemokines. Many viral proteins encoded by coronaviruses (red: SARS-CoV, green: MERS-CoV, black: multiple human coronaviruses) antagonize various steps of this antiviral response.

Figure 2

Protective and Pathogenic Roles of Type I IFNs during Coronavirus Infection Both viral and host factors can affect the timing of IFN response. When the initial viral burden is low (left), IFNs can be induced early and clear the infection effectively. High viral load (right) may strongly suppress the IFN response due to viral evasion mechanisms, causing its delayed induction. Alternatively, IFN induction may be compromised in older hosts. When the IFN response is insufficient to control initial viral replication, late onset IFN could lead to inflammation and lung injury.

Figure 3

Therapeutic Aims with Type I and Type III IFNs during the Progression of COVID-19 (Α) Prophylactic intranasal administration or inhalation of recombinant IFNs, particularly type III IFNs (IFN-λ), can act to restrict viral replication in the upper airway, reducing viral spread to the lungs and transmission. (Β) When initial control fails and virus reaches the lung, the host may benefit from additional IFNs, including the more potent type I IFNs (IFN-α, IFN-β). Given that our natural IFN response may be lacking at this early stage, exogenous IFNs might help control infection and prevent viral dissemination. (C) In the late stage of the disease, IFNs must be used with caution to not exacerbate inflammation and tissue damage. IFN-λ could continue to activate localized antiviral protection without triggering a systemic response.