Chronic IL-33 expression predisposes to viral-induced exacerbations of asthma by increasing type-2 inflammation and dampening antiviral immunity

Background: Rhinovirus infection triggers acute exacerbations of asthma. IL-33 is an instructive cytokine of type-2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic subjects.Objective: To determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vivo human primary airway epithelial cells (AECs).Methods: To model disease onset, progression, and chronicity, mice were exposed to pneumonia virus of mouse and cockroach extract in early-life and later-life, then challenged with rhinovirus. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic and healthy patients, and treated with anti-IL-33 following RV infection.Results: Anti-IL-33 decreased type-2 inflammation in all phases of disease; however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high and rhinovirus challenge exacerbated the type-2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity and anti-IL-33, but not dexamethasone, promoted antiviral IFN expression and decreased viral load. RV replication was higher and IFN-lambda lower in asthmatic compared to healthy AECs. Anti-IL-33 lowered RV replication and increased IFN-λ at the gene and protein level.Conclusion: Anti-IL-33 or dexamethasone suppressed the magnitude of type-2 inflammation during a rhinovirus-induced acute exacerbation, however only anti-IL-33 boosted antiviral immunity and lowered viral replication. The latter phenotype was replicated in RV infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defence.Key words IL-33; rhinovirus; asthma; exacerbation; antivira