A fungal protease allergen provokes airway hyper-responsiveness in asthma

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

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Administration, Inhalation
  • Allergens / administration & dosage
  • Allergens / immunology*
  • Animals
  • Aspergillus fumigatus / chemistry*
  • Aspergillus fumigatus / immunology
  • Asthma / immunology*
  • Asthma / pathology
  • Bacterial Proteins / administration & dosage
  • Bacterial Proteins / immunology*
  • Bronchi / drug effects
  • Bronchi / immunology
  • Bronchi / pathology
  • Bronchoconstriction / drug effects*
  • Bronchoconstriction / immunology
  • Calcium / immunology
  • Calcium / metabolism
  • Disease Models, Animal
  • Endopeptidases / administration & dosage
  • Endopeptidases / immunology*
  • Extracellular Matrix / chemistry
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / immunology
  • Female
  • Fungal Proteins / administration & dosage
  • Fungal Proteins / immunology*
  • Gene Expression
  • Histamine / biosynthesis
  • Histamine / immunology
  • Humans
  • Immunoglobulin E / biosynthesis*
  • Mice
  • Mice, Inbred BALB C
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / immunology
  • Myocytes, Smooth Muscle / pathology
  • Primary Cell Culture
  • Trachea / drug effects
  • Trachea / immunology
  • Trachea / pathology
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / immunology
  • rhoA GTP-Binding Protein

Substances

  • Allergens
  • Bacterial Proteins
  • Fungal Proteins
  • Immunoglobulin E
  • Histamine
  • Endopeptidases
  • alkaline protease
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • Calcium