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Nat Commun. 2015 Apr 13;6:6763. doi: 10.1038/ncomms7763.

A fungal protease allergen provokes airway hyper-responsiveness in asthma.

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Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, Maryland 20892-8305, USA.
Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, 125 South 31st Street, Philadelphia, Pennsylvania 19104-3413, USA.
Protein Chemistry, Research Technologies Branch, Twinbrook I, 5640 Fishers Lane Room 1012 NIAID/NIH, Rockville, Maryland 20852-1737, USA.
Institut universitaire de cardiologie et pneumologie de Québec (Laval University), Département multidisciplinaire de pneumologie et de chirurgie thoracique de l'IUCPQ, L35312725, chemin Sainte-Foy, Québec, Canada G1V 4G5.


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 Ca(2+) 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.

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