Innate airway immune response to fungal allergens

Fungi are ubiquitous in our environment, and inhaled exposure of their spores is associated with the development of upper and lower respiratory airway diseases including asthma and chronic rhinosinusitis (CRS). CRS and asthma associated with fungal sensitization also tend to be more severe compared with other endotypes. Alternaria and Aspergillus species have specifically been recognized as the primary fungal allergens that stimulate a robust innate immune response, potentially leading to allergic sensitization and type 2 inflammation. Other fungi, such as Cladosporium, Penicillium, and Candida, are also associated with airway inflammatory disease. Fungal proteases disrupt airway mucosal barriers and activate protease-activated receptors (PARs), leading to a release of alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), that drive innate type 2 inflammatory responses. Recent studies have also shown that protease allergens can cleave the protease-sensing domain of IL-33, generating a more active form. Alarmins activate innate immune cells including group 2 innate lymphoid cells (ILC2s), dendritic cells, mast cells, and eosinophils which contribute to epithelial mucus production, airway hyperresponsiveness, and tissue remodeling. This review aims to detail mechanisms of fungal allergen-induced airway inflammation and identify gaps in understanding and therapeutic opportunities.