Pulmonary ILC2 Priming as a Link Between Severe Early-Life RSV Bronchiolitis and Asthma

Severe respiratory syncytial virus (RSV) bronchiolitis in infancy is associated with increased childhood asthma risk, but the mechanisms that sustain airway vulnerability remain unresolved. Airway samples from infants with severe RSV disease and experimental models show robust IL-33 responses and pulmonary group 2 innate lymphoid cell (ILC2) activation during acute infection. Additionally, neonatal IL-33 and allergen-rechallenge studies demonstrate that ILC2s can persist and acquire memory-like properties. These observations support, but do not establish, a model in which severe lower-airway RSV disease primes ILC2s or their tissue niche for exaggerated responses to later allergens. Beyond limited interferon control and prolonged epithelial injury, which may amplify IL-33/ST2 signaling during a developmental window when long-lived lung ILC2 populations are established, we focus on additional candidate mechanisms that could sustain this priming. These include metabolic pathways governing glycolysis, lipid utilization, iron uptake, and mitochondrial function; epigenetic mechanisms involving chromatin remodeling and histone or DNA modifications; and neuroimmune signals that regulate ILC2 activation and recall. Direct evidence that RSV induces durable, cell-intrinsic metabolic, epigenetic, or neuroimmune reprogramming of infant pulmonary ILC2s is currently lacking. Longitudinal ILC2 profiling and adoptive transfer of RSV-experienced versus control ILC2s are needed to test this model. Maternal vaccination and long-acting monoclonal antibodies now provide an opportunity to determine whether preventing severe early-life RSV disease alters airway immune programming and subsequent asthma risk.