Rhinovirus (RV) infections are the most common cause of asthma exacerbations and our previous studies with experimental RV-A16 inoculations demonstrate the ability of this model to recapitulate the physiological and immune consequences of natural infections. What has never previously been appreciated is that asthmatics consistently also demonstrate recurrence of upper and lower airway symptoms peaking 2-3 weeks post- inoculation. RV inoculation in asthmatics is associated with rapid development of an eosinophilic response in the airway that peaks at 2-4 days post-infection (dpi). This increase in eosinophilic inflammation evolves too rapidly to be explained by an adaptive immune response, however, the ability of the innate immune system to exacerbate an established type 2 inflammatory state is recognized. This reflects generation by a dysmatured epithelial cells (EpC) compartment of a type 2 inflammation-promoting milieu including release of the cytokines interleukin (IL)-25, IL-33, and TSLP. IL-25 has recently been recognized to be exclusively produced by a differentiated EpC termed the solitary chemosensory cell (SCC). All 3 cytokines activate immune cells of the airway, including innate lymphoid 2 cells (ILC2s). But other cells including mast cells express their receptors and will respond with secretion of IL-5 and IL-13. Along with enhanced expression of other epithelial-derived eosinophil-activating cytokines, this explains the exacerbation of eosinophilic inflammation and symptoms observed within 2-3 days of the inoculation. In the proposed studies, we are particularly eager to explore mechanisms responsible for the protracted worsening of airway symptoms and inflammation. The increase in IL-13 production will promote the further differentiation of goblet cells and SCCs and we predict that these will comprise an increasingly high proportion of airway EpCs over 2-3 weeks. SCC-derived IL-25 (and other cytokines) will then promote the expansion of mast cells and ILC2s. However, this late recurrence of asthma symptoms is occurring in the presence of ongoing aeroallergen exposure. Our studies have demonstrated the ability of RV to enhance adaptive immune responses to bystander aeroallergens. The interaction of allergens with expanded populations of mast cells and allergen-specific CD4+ tissue resident memory (TRM) lymphocytes will establish a milieu that we propose underlies the protracted worsening of inflammation and symptoms. In summary, we hypothesize that RV infection results in the rapid induction of an inflammatory response by a dysmatured epithelial compartment, which leads to the exacerbation of a type 2 inflammatory state that is responsible for the rapid development RV-induced asthma exacerbations. More importantly, we propose that this RV infection will lead to the delayed expansion of SCCs, ILC2s, CD4+ TRM lymphocytes, and mast cells, that leads to the recurrent/protracted worsening of respiratory symptoms and enhances susceptibilit...