A fungal protease allergen provokes airway hyper-responsiveness in asthma

Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine—also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca2+ sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness. Airway hyper-responsiveness, a hallmark of asthma, is often associated with sensitization to fungi. Here, the authors show that a fungal protease allergen Asp f13/Alp1 from Aspergillus fumigatuscan promote airway hyper-responsiveness in asthma via its effect on the airway smooth muscle cells.