Aeroallergen-induced IL-33 Predisposes to Respiratory Virus-induced Asthma by Dampening Type I and III Interferon Production

Frequent viral lower respiratory infections (vLRI) and allergic sensitization in early life are independent risk factors for asthma onset, yet together significantly increase the development of persistent asthma.  We developed an experimental model of asthma to investigate this synergy.  Neonatal BALB/c mice were inoculated with low dose pneumonia virus of mouse (PVM; 1pfu) then exposed to low dose (1µg) cockroach antigen or vehicle control at 3 days post infection (dpi).  Some mice were re-infected 6 weeks later and exposed to weekly doses of allergen.  Virus and allergen co-exposure was critical in both early and later life for disease onset and progression, including airway hyperreactivity, airway remodelling and type 2 inflammation. Allergen exposure during primary vLRI increased IL-33 release and impaired antiviral cytokine production, leading to increased epithelial viral burden, Th2-type inflammation and airway smooth muscle growth. Neutralisation of IL-33 in early life prevented type 2 inflammation, airway remodelling and reversed the dampened interferon response mediated by cockroach antigen.  Substitution of allergen with exogenous IL-33 attenuated antiviral cytokines, elevated viral load and promoted airway remodelling.  Mechanistically, we found that IL-33 degraded IRAK1 to dampen type I IFN production by plasmacytoid DC.  In summary, we identify a novel role for IL-33 in regulating antiviral immunity and as a target to attenuate the synergistic interplay between two important environmental insults in the onset and progression of asthma.