In respiratory viral infections, disease severity is determined mainly by lung epithelial damage, which results from both direct viral effects and immune-mediated injury. Epithelial damage disrupts barrier function, contributing to acute respiratory distress syndrome (ARDS), pneumonia, and bacterial superinfections. Therefore, epithelial tissue regeneration is essential for restoring lung function.
Interferons (IFNs) play a central role in antiviral defence. IFN-α/β and IFN-λ are produced in response to viral recognition and activate ISG genes with antiviral functions in both infected and neighbouring cells. However, the IFN-α receptor is broadly expressed on immune cells, so IFN-α signalling can drive excessive inflammation and tissue injury, as seen in influenza and SARS-CoV-1. In contrast, IFN-λ receptors are mainly expressed on epithelial cells, restricting IFN-λ action to the site of infection and providing protection without systemic inflammation. Yet IFNs not only provide antiviral defense but also suppress cell division and promote apoptosis. The link between lung repair and IFN signaling remained unclear until recently.
Endogenous IFN-λ Restricts Proliferation of Alveolar Epithelial Cells During Recovery
In mice, influenza infection triggered weight loss, immune cell infiltration, and lung injury. Recovery coincided with epithelial regeneration. To assess repair, scientists used the marker Ki67, which reflects cell division. Normally, alveolar type II epithelial cells (AT2) divide slowly; however, following viral damage, they begin proliferating actively by days 5–7, coinciding with weight recovery and improved health.
Interferons peaked by day 2, with IFN-λ produced for longer and at higher levels than IFN-α/β. By days 7–8, only IFN-λ remained detectable in the lungs, overlapping with the onset of epithelial regeneration. Administration of equivalent doses of IFN-α, IFN-β, or IFN-λ during recovery reduced AT2 proliferation, independent of viral load. The effect of IFN-λ did not depend on neutrophils and was observed in both Mx1-deficient and Mx1-functional mice.
Mice lacking IFNAR or IFNLR receptors showed enhanced AT2 proliferation during recovery, indicating a direct antiproliferative effect of interferons on lung epithelium. Viral control was not impaired due to redundancy of IFN-I and IFN-III antiviral mechanisms. Further, IFNAR signaling was required for IFN-λ induction during influenza infection. Antibody blockade of IFNAR early in infection preserved IFN-λ production but did not affect epithelial proliferation, confirming that endogenous IFN-λ directly suppresses lung regeneration.
Interferons Suppress Differentiation and Growth of Airway Epithelial Cells via p53 Activation
In mouse airway epithelial cell (AEC) cultures modeling lung repair, all three interferon subtypes (IFN-α, IFN-β, IFN-λ) suppressed growth, with IFN-β and IFN-λ having the most potent effects. They increased apoptosis and necrosis, with growth suppression limited to actively dividing cultures, indicating that cell cycle disruption is the underlying mechanism.
IFN-β and IFN-λ also reduced the expression of genes linked to multiciliated and secretory cell differentiation, while the basal cell marker Krt5 remained unchanged or increased under IFN-λ treatment. The number of multiciliated cells decreased after IFN-λ treatment, but not after IFN-α or IFN-β treatment. In IFNLR1-deficient mice, the number of multiciliated cells increased during recovery, indicating that IFN-λ impairs the differentiation of basal cells during lung repair.
Gene expression analysis revealed that prolonged exposure to IFN-β and IFN-λ altered AEC transcription, activating pathways associated with cell cycle arrest and apoptosis. The key regulator was p53: in Tp53 knockout AECs, interferons no longer suppressed growth, differentiation, or p53-dependent gene expression. In wild-type mice and IFNAR-deficient mice with neutrophil depletion, IFN-β and IFN-λ, but not IFN-α, markedly increased p53 expression in lung epithelial cells during recovery, confirming that their antiproliferative effects are mediated via p53.
IFN-λ Impairs Lung Barrier Function and Increases Susceptibility to Bacterial Superinfection
Interferon signalling, particularly IFN-λ, reduces epithelial proliferation and differentiation during the recovery process. IFNLR-deficient mice displayed enhanced proliferative and differentiation pathways, reduced lung damage, and less inflammation. Following S. pneumoniae superinfection, these mice had improved survival, demonstrating that IFN-λ compromises lung barrier function and increases susceptibility to bacterial superinfection.
Conclusion
While administration of all IFN subtypes suppressed epithelial proliferation during recovery from influenza, only endogenous IFN-λ impaired lung repair. This effect is explained by its high, prolonged production and activation of antiproliferative pathways, including p53.
Thus, IFN-λ provides early antiviral protection without the systemic inflammation associated with IFN-α/β, but at later stages, it limits lung regeneration. Therapeutic strategies for respiratory viral infections must account for both the timing and duration of the interferon response.
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Reference
Type I and III interferons disrupt lung epithelial repair during recovery from viral infection
