Interferon Lambda: Modulating Immunity in Infectious Diseases

Abstract

Interferon lambdas (IFN-λs; IFNL1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. IFN-λs act by binding to the heterodimeric IFN-λ receptor (IFNLR), activating a STAT phosphorylation-dependent signaling cascade. Thereby hundreds of IFN-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. When compared to the well-characterized IFN-α signaling cascade, three important differences have been discovered. First, the IFNLR is not ubiquitously expressed: in particular, immune cells show significant variation in the expression levels of and susceptibilities to IFN-λs. Second, the binding affinities of individual IFN-λs to the IFNLR varies greatly and are generally lower compared to the binding affinities of IFN-α to its receptor. Finally, genetic variation in the form of a series of single-nucleotide polymorphisms (SNPs) linked to genes involved in the IFN-λ signaling cascade has been described and associated with the clinical course and treatment outcomes of hepatitis B and C virus infection. The clinical impact of IFN-λ signaling and the SNP variations may, however, reach far beyond viral hepatitis. Recent publications show important roles for IFN-λs in a broad range of viral infections such as human T-cell leukemia type-1 virus, rotaviruses, and influenza virus. IFN-λ also potentially modulates the course of bacterial colonization and infections as shown for Staphylococcus aureus and Mycobacterium tuberculosis. Although the immunological processes involved in controlling viral and bacterial infections are distinct, IFN-λs may interfere at various levels: as an innate immune cytokine with direct antiviral effects; or as a modulator of IFN-α-induced signaling via the suppressor of cytokine signaling 1 and the ubiquitin-specific peptidase 18 inhibitory feedback loops. In addition, the modulation of adaptive immune functions via macrophage and dendritic cell polarization, and subsequent priming, activation, and proliferation of pathogen-specific T- and B-cells may also be important elements associated with infectious disease outcomes. This review summarizes the emerging details of the IFN-λ immunobiology in the context of the host immune response and viral and bacterial infections.

IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

“…IL10RB is ubiquitously expressed, whereas IL28RA expression is restricted and interestingly, it is highly expressed on lung epithelial cells [4] and alveolar macrophages [5]. When a virus is seen by the pattern recognition receptors which are found on macrophages and epithelial cells, IFNL gene expression is stimulated via various signalling pathways [6]. This leads to increased circulating IFNL3 which interacts with the IFNL receptor expressed on lung, intestinal and liver cells, and via the JAK-STAT signalling cascade induces interferon stimulated genes which in turn influence viral replication [6].…”

“…When a virus is seen by the pattern recognition receptors which are found on macrophages and epithelial cells, IFNL gene expression is stimulated via various signalling pathways [6]. This leads to increased circulating IFNL3 which interacts with the IFNL receptor expressed on lung, intestinal and liver cells, and via the JAK-STAT signalling cascade induces interferon stimulated genes which in turn influence viral replication [6]. A series of single nucleotide polymorphisms (SNPs) in the IFNL3/4 gene region have been described [7][8][9] and associated with variable IFNL3/4 gene expression [10][11][12][13].…”

Immunity against hepatitis E virus infection: Implications for therapy and vaccine development

“…Once produced, IFNs signal via autocrine and paracrine routes to combat the invading viruses. IFNs consist of 3 different types, type I (IFNα, IFNβ, IFNδ, and other sub‐types), type II (IFNγ, the only member), and type III (IFNλ1, IFNλ2, IFNλ3, and IFNλ4) . Binding of IFNs to their corresponding receptors activates their common downstream signaling pathway, involving classical Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) pathway.…”

“…Following activation by type I and III IFNs, STAT1 and STAT2 proteins are phosphorylated and associate with IRF9. This complex, designated as interferon stimulated gene factor 3 (ISGF3), then translocates to the nuclues, to induce transcription of hundreds of IFN‐stimulated genes (ISGs) . ISGs are the ultimate effector antiviral molecules which cooperatively establish an antiviral state against diverse types of viruses .…”

Hypothiocyanous Acid Suppresses PolyI:C-Induced Antiviral Responses by Modulating IRF3 Phosphorylation in Human Airway Epithelial Cells

“…During RNA virus infection, double-stranded RNA (dsRNA) is recognized by TLR3, RIG-I, and melanoma differentiation-associated gene 5 (MDA-5) to trigger appropriate antiviral responses, including the production of various cytokines and inflammatory response factors . In particular, the production of type I and III interferons (IFNs; IFN-α, Ι FN-β and IFN-λ) induced in the early phase after viral infection is important for limiting viral replication and spread (Kawai and Akira 2006;Syedbasha and Egli 2017). In addition to type I and III IFN production, virus-infected cells undergo apoptosis in an attempt to limit the spread of the disease (Shen and Shenk 1995).…”