Interferon Lambda: The Next Frontier in Antiviral Therapy?

Abstract

Type III interferons (IFN-λ) are the most recently identified members of the interferon family, distantly related to type I interferons and members of the interleukin-10 (IL-10). Unlike type I interferons, which have broadly distributed cellular receptors, IFN-λ signals through a heterodimeric receptor complex with primary expression on epithelial cells. This restricted receptor distribution makes IFN-λ a favorable candidate for therapeutic and antiviral applications with reduced side effects. In this review, we describe the molecular structure, signaling mechanisms, and the role of IFN-λ in the innate immunity of epithelial tissue, which are its primary sites of action. Moreover, this review will summarize and critically examine the antiviral potential of IFN-λ based on all published clinical trials conducted for the treatment of COVID-19, and hepatitis B, C and D virus. Furthermore, this review suggests IFN-λ as a promising therapeutic recombinant protein, with special emphasis on its potential for production using alternative expression and advanced drug delivery systems. To emphasize its potential as a therapeutic intervention, the design and engineering of recombinant IFN-λ will be presented, with a focus on its lower side-effect profile compared to Type I interferons.

Keywords: COVID-19; antiviral therapy; cytokines; hepatitis B; hepatitis C; hepatitis D; interferon lambda.

Figure 1

Historical overview: major milestones of interferon research and workflow of current review. IFN: Interferon; COVID-19: coronavirus disease 2019; PEG: pegylated.

Figure 2

Structural representations of type III interferons. (A) X-ray crystallographic structure of IFN-λ1 (PDB ID: 3OG4). (B) Predicted structure of IFN-λ2 generated by AlphaFold (Model ID: AF-Q8IZJ0-F1). (C) X-ray crystallographic structure of IFN-λ3 (PDB ID: 4HHC). (D) Predicted structure of IFN-λ4 generated by AlphaFold (Model ID: AF-K9M1U5-F1).

Figure 3

Signaling pathways induced by type I and type III Interferons. Ligand binding triggers the phosphorylation and activation of two kinases, Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which in turn leads to phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2. Phosphorylated STAT1 and STAT2 form heterodimers and associate with interferon regulatory factor 9 (IRF9). This complex (STAT1, STAT2 and IRF9) is then imported into the nucleus triggering enhanced transcriptional activity of interferon-stimulated genes (ISGs). DC: dendritic cell.