Critical role for IL-33 in the onset and progression of experimental asthma induced by concomitant virus infection and allergen exposure (#196)
Frequent, severe wheezy lower respiratory tract viral infections and allergic sensitisation in early life are independently associated with the onset of asthma, and positively interact to markedly increase asthma risk. We have developed a model to interrogate this synergy by inoculating neonatal BALB/c mice with low dose pneumonia virus of mouse (PVM; 1pfu) then exposure to a submaximal dose of cockroach antigen (CRE, 1µg) 3 days post infection (dpi). CRE exposure following viral infection reduced antiviral immunity (IFN-α, IFN-λ, IL-12p40) and increased viral load in the airway epithelium. Moreover, plasmacytoid dendritic cells stimulated in vitro with CRE exhibited impaired antiviral function. Furthermore, co-exposure to PVM and CRE promoted type 2 inflammation (elevated IL-33, recruitment of eosinophils and type 2 ILCs) and airway remodelling (airway smooth muscle and collagen deposition) at 10dpi, compared with PVM infection alone. Immunoneutralisation of IL-33 prevented the induction of ILC2s, eosinophilia and importantly inhibited airway remodelling in co-exposed mice. Furthermore, exposure to CRE in early life significantly altered the immune response to the virus and allergen in reinfection. Asthma pathology (airway hyperresponsiveness, airway remodelling, eosinophilia, mast cell hyperplasia) following PVM reinfection (at day 49) and CRE challenge (at days 52, 59, 66 and 80) in later life was significantly elevated in co-exposed neonates. IL-33 blockade in primary and secondary infection significantly reduced all hallmark features of asthma. Our findings demonstrate that by reducing antiviral immunity, allergen exposure early in life increases viral load, and primes toward a Th2 response that drives the progression of asthma in reinfection. Furthermore, we highlight a critical role for IL-33 underlying this virus-allergen synergy and are able to prevent disease onset by targeting this pathway.