A fungal protease allergen provokes airway hyper-responsiveness in asthma

Nariman A. Balenga, Michael Klichinsky, Zhihui Xie, Eunice C. Chan, Ming Zhao, Joseph Jude, Michel Laviolette, Reynold A. Panettieri and Kirk M. Druey ()
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Nariman A. Balenga: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH
Michael Klichinsky: Pulmonary, Airways Biology Initiative, University of Pennsylvania
Zhihui Xie: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH
Eunice C. Chan: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH
Ming Zhao: Protein Chemistry, Research Technologies Branch, Twinbrook I
Joseph Jude: Pulmonary, Airways Biology Initiative, University of Pennsylvania
Michel Laviolette: Institut universitaire de cardiologie et pneumologie de Québec (Laval University)
Reynold A. Panettieri: Pulmonary, Airways Biology Initiative, University of Pennsylvania
Kirk M. Druey: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7763

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