The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

Abstract

Type I interferons (IFN-I) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman, who showed that IFN-Is possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved, and widely used in a pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C, and some forms of cancer. Preliminary clinical data has supported its effectiveness against potential pandemic pathogens such as Ebola and SARS. Still, more efficient and specific drugs have taken its place in treating such diseases. The COVID-19 global pandemic has again lifted the status of IFN-Is to become one of the more promising drug candidates, with initial clinical trials showing promising results in reducing the severity and duration of the disease. Although SARS-CoV-2 inhibits the production of IFNβ and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I-receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Furthermore, I discuss how these may guide the optimized use IFN-Is in combatting COVID-19.

Keywords: COVID-19; differential activity; inflammation; signaling; type I interferon.

Figure 1

The interferon response is initiated by IFN-I binding to the extracellular domains of IFNAR1 and IFNAR2. Following ternary-complex formation, the associated JAK kinases cross-phosphorylate each other as well as the associated STATs and tyrosine residues on the intracellular domains of the receptors. Upon phosphorylation the STATs are released and are transported to the nucleus. The STAT1/STAT2/IRF9 complex is strongest associated with IFN-I induced gene induction, albeit other STAT complexes are activated as well (see Figure 2 for details). The STAT complexes serve as transcription factors for many IFN-I induced genes. Three main feedback mechanisms quell IFN-I activity: Receptor Ubiquitination, resulting in receptor endocytosis (which is initiated within minutes from IFN-I induction) and SOCS and USP18, which are IFN-I induced genes and thus their feedback relates to their production to high levels (which takes hours).

Figure 2

Ternary, IFN-I/IFNAR1/IFNAR2 complex formation results in the activation of multiple STAT complexes that serve as transcription factors for different genes. The activated STATs and IFN-I regulated genes vary between different cells, IFN-I subtype, its concentration and duration of activation, result in a pleiotropy of responses.

Figure 3

Genes which expression was upregulated by over 3-fold in the following cell lines: HeLa, T47D, K562 and OVCAR3. (A) venn diagram of the upregulated genes. (B) STRING: functional protein association network analysis of upregulated genes in all 4 cell lines (53 genes). According to STRING and GO analysis, the commonly upregulated genes have a strong antiviral signature. The top GO terms (FDR <10⁻²⁵) are response to type I interferon, innate immune response, response to virus, defense response and immune system process. It is interesting to note that antiviral genes constitute most of the upregulated genes common to all 4 cell lines. Antiviral genes are also the majority of upregulated genes in K562 and T47D cells. Conversely, OVCAR3 and HeLa cells have many unique upregulated genes, many of them related to immunomodulatory functions, cell cycle, apoptosys and more.

Figure 4

SARS-CoV-2 has multiple effects on the immune system, including inhibition of IFNβ production, which results in ISGs not to be produced, CD4+ and CD8+ exhaustion and increased levels of pro-inflammatory proteins (TNFα, IL6, NF-kB). Currently, the most promising drugs against COVID-19 include IFN-Is, anti-inflammatory and antiviral drugs, protease inhibitors, antibodies, SARS-CoV2 – ACE2 (receptor) binding inhibitors and more.