We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.

RSV bronchiolitis causes significant infant mortality. Bronchiolitis is characterised by airway epithelial cell (AEC) death, however the mode of death remains unknown. Objectives:To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via high mobility group box 1 (HMGB1) release. Methods:Nasopharyngeal samples were collected from children presenting to hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine pneumovirus respectively. Necroptosis was determined via viability assays and immunohistochemistry for receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL) and caspase-3. Necroptosis was blocked using pharmacological inhibitors, and RIPK1 kinase-dead knock-in mice. Measurements and Main Results:HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased pRIPK1 and pMLKL, but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSVinduced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice, Pneumovirus infection up-regulated RIPK1 and MLKL expression in the airway epithelium at 8-10 days post infection; coinciding with AEC sloughing, HMGB1 release, and

Lynch et al. provide evidence of a causal relationship between RSV-bronchiolitis and asthma development and highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to confer protection against severe bronchiolitis and asthma.