The Key Roles of Interferon Lambda in Human Molecular Defense against Respiratory Viral Infections

Abstract

Interferons (IFN) are crucial for the innate immune response. Slightly more than two decades ago, a new type of IFN was discovered: the lambda IFN (type III IFN). Like other IFN, the type III IFN display antiviral activity against a wide variety of infections, they induce expression of antiviral, interferon-stimulated genes (MX1, OAS, IFITM1), and they have immuno-modulatory activities that shape adaptive immune responses. Unlike other IFN, the type III IFN signal through distinct receptors is limited to a few cell types, primarily mucosal epithelial cells. As a consequence of their greater and more durable production in nasal and respiratory tissues, they can determine the outcome of respiratory infections. This review is focused on the role of IFN-λ in the pathogenesis of respiratory viral infections, with influenza as a prime example. The influenza virus is a major public health problem, causing up to half a million lethal infections annually. Moreover, the virus has been the cause of four pandemics over the last century. Although IFN-λ are increasingly being tested in antiviral therapy, they can have a negative influence on epithelial tissue recovery and increase the risk of secondary bacterial infections. Therefore, IFN-λ expression deserves increased scrutiny as a key factor in the host immune response to infection.

Keywords: influenza; innate immunity; interferon stimulated genes; interferons-α/β; interferons-λ; respiratory viruses.

Figure 1

Virus entry initiates the interferon (IFN) response. Upon entering a cell, virus activates Pattern Recognition Receptors (PRR) that include the Toll-like receptors (TLR), the RIG-I-like receptors (RLR), the NOD-like receptors, and some cytosolic nucleic acid receptors. These PRR activate adaptor molecules like MyD88, Mal, TRIF, and TRAM. PRR also activate the MAPK pathway. The Adaptor molecules activate Transcription factors like IRF-3, IRF-7 and NF-kB. IFN mRNA are transcribed and they express the type I, type II (not shown), and type III IFN. Type I and Type III IFN bind to distinct receptors that activate similar signaling pathways and transcriptional responses. The heterodimeric IFN receptors signal through the JAK/STAT pathways to form a complex with IRF-9 to initiate the expression of hundreds of Interferon stimulated genes (ISG). The ISG are peptidic antivirals that interfere with virus replication.