Section 3: IFN-lambda as an antiviral drug (from DOI: 10.1084/jem.20200653)
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From publication: "COVID-19 and emerging viral infections: The case for interferon lambda" published as J. Exp. Med.; 2020 05 04 ; 217 (5)
https://doi.org/10.1080/22221751.2020.1735265
Section 3: IFN-lambda as an antiviral drugIFN-lambda as an antiviral drug
For decades, type I IFNs (IFN-alpha/beta) have been explored as mediators of rapid, innate antiviral protection. In 2003, a novel group of three cytokines, now known as type III IFNs (IFN-lambdas), was discovered that act independently of type I IFNs to establish antiviral resistance in cells. An additional member of this family (IFN-lambda4) was discovered in 2013. Most of the information on the function of IFN-lambdas has been generated using mouse models and thus has to be critically evaluated in relation to human disease. The distinctive actions of type I and type III IFNs are achieved through the engagement of separate nonoverlapping heteromeric receptor complexes: IFNAR complex (with IFNAR1/IFNAR2 subunits) for all type I IFNs and IFNL complex (with IFNLR1/IL10R2 subunits) for all type III IFNs (Fig. 1). Signaling pathways and sets of IFN-stimulated genes (ISGs) induced by these IFNs are remarkably similar but not redundant. IFNAR is expressed on all cells, while IFNLR, limited by IFNLR1 expression, is restricted to epithelial cells and a subset of immune cells, including neutrophils. Due to these specific expression patterns, type I IFNs provide a systemic response, and IFN-lambdas guard epithelial surfaces (; Fig. 1).
Type I IFNs have been used to treat chronic hepatitis C virus and hepatitis B virus infection and may have the potential to protect patients during outbreaks of other viruses. However, these treatments have significant systemic side effects due to the ubiquitous expression of IFNAR. In mice, IFN-lambda was found to be more effective than IFN-alpha in preventing and treating influenza virus infection, with no increase in inflammation and tissue damage as compared with IFN-alpha. IFN-lambda was also more potent than IFN-alpha in restricting viral dissemination from nasal epithelium to the upper respiratory tract. Clinical trials of IFN-lambda for the treatment of chronic hepatitis C virus infection documented fewer and milder side effects, but equal efficacy, when compared with IFN-alpha-based therapies. These studies suggest specific advantages for IFN-lambdas as antiviral therapeutics at epithelial surfaces.
