ASTHMA exacerbations and related fatalities are frequently linked to respiratory viral infections. One key factor in this process is the defective production of type I interferons (IFNs), which are critical for host defense against viruses. Both type I and III IFNs play a crucial role in immune responses, and their deficiency has been implicated in severe respiratory infections, including COVID-19.
Mast cells, which are abundant in the airways of asthmatic individuals, act as first responders to viral infections by producing cytokines, chemokines, and lipid mediators. These immune cells influence both structural airway cells and the broader immune environment. A cytokine-rich setting, particularly one abundant in interleukin-4 (IL-4) and interleukin-5 (IL-5), significantly alters mast cell function. While IL-4 has been shown to enhance IFN production during viral infections, the role of IL-5 has remained less clear.
Recent studies demonstrate that IL-5 treatment substantially increases type I and III IFN production in mast cells exposed to respiratory viruses such as human coronavirus OC43, respiratory syncytial virus (RSV), and reovirus. This occurs through the regulation of B-cell lymphoma 2 (BCL2) and endothelial PAS domain protein 1 (EPAS1), both of which promote mast cell survival. Single-cell RNA sequencing and previous clinical studies indicate that pharmacological IL-5 inhibition in asthmatic patients is associated with reduced EPAS1 expression.
IL-5, a key mediator in allergic inflammation, has become a target for biological treatments like mepolizumab, reslizumab, and benralizumab, which neutralize IL-5 or block its receptor. However, the broader impact of these therapies on immune cells beyond eosinophils remains under investigation. Evidence suggests that IL-5 blockade could alter mast cell survival and antiviral responses, particularly through the EPAS1 pathway, which regulates IFN production and immune cell recruitment.
With IL-5 inhibitors already in clinical use, it is crucial to assess their effects beyond eosinophils, including on mast cell function and broader immune responses. While IL-5 inhibition may improve allergic inflammation control, its potential impact on antiviral immunity requires further study to ensure comprehensive and effective asthma management.
Katie Wright, EMJ
Reference
Barra J et al. Interleukin-5 enhances human mast cell survival and interferon responses to viral infection. J Allergy Clin Immunol. 2025;DOI:10.1016/j.jaci.2025.02.025.
