Dynamics of IFN-ß responses during respiratory viral infection: insights for therapeutic strategies

Abstract

Rationale: Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and COPD. IFN-β is a key component of the innate immune response to viral infection. However, in the recent INEXAS clinical trial, on-demand IFN-β treatment of asthmatics failed to prevent severe exacerbations.

Objectives: The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential anti-viral therapy.

Methods: Monocyte-derived macrophages (MDMs), alveolar macrophages and primary bronchial epithelial cells (PBECs) were isolated from healthy controls and COPD patients and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by % nucleoprotein 1 positive (NP1+) cells using flow cytometry. Viral RNA shedding and interferon stimulated gene expression were measured by qPCR. Production of inflammatory cytokines was measured using MSD.

Measurements and Main Results: Adding IFN-β to MDMs, alveolar macrophages and PBECs prior to, but not after, infection reduced %NP1+ cells by 85%, 56% and 66%, respectively (p<0.05). The effect of IFN-β lasted up to 1 week in MDMs and 72 h in PBECs after IFN-β removal; this was similar between health and COPD. Exogenous IFN-β did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1β production by PBECs.

Conclusions: In vitro modelling of IFN-β dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-β to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-β in asthma and COPD.