title: Aspergillus fumigatus proteases, Asp f 5 and Asp f 13, are essential for airway inflammation and remodelling in a murine inhalation model.
abstract: BACKGROUND
  In susceptible individuals, exposure to Aspergillus fumigatus can lead to the development of atopic lung diseases such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). Protease allergens including Asp f 5 and Asp f 13 from Aspergillus fumigatus are thought to be important for initiation and progression of allergic asthma.
  
  
  OBJECTIVE
  To assess the importance of secreted protease allergens Asp f 5 (matrix metalloprotease) and Asp f 13 (serine protease) in Aspergillus fumigatus-induced inflammation, airway hyperactivity, atopy and airway wall remodelling in a murine model following chronic exposure to secreted allergens.
  
  
  METHODS
  BALB/c mice were repeatedly intranasally dosed over the course of 5 weeks with culture filtrate from wild-type (WT), Asp f 5 null (∆5) or Asp f 13 null (∆13) strains of Aspergillus fumigatus. Airway hyper-reactivity was measured by non-invasive whole-body plethysmography, Th2 response and airway inflammation by ELISA and cell counts, whilst airway remodelling was assessed by histological analysis.
  
  
  RESULTS
  Parent WT and ∆5 culture filtrates showed high protease activity, whilst protease activity in ∆13 culture filtrate was low. Chronic intranasal exposure to the three different filtrates led to comparable airway hyper-reactivity and Th2 response. However, protease allergen deleted strains, in particular ∆13 culture filtrate, induced significantly less airway inflammation and remodelling compared to WT culture filtrate.
  
  
  CONCLUSIONS
  Aspergillus fumigatus-secreted allergen proteases, Asp f 5 and Asp f 13, are important for recruitment of inflammatory cells and remodelling of the airways in this murine model. However, deletion of a single allergen protease fails to alleviate airway hyper-reactivity and allergic immune response. Targeting protease activity of Aspergillus fumigatus in conditions such as SAFS or ABPA may have beneficial effects in preventing key aspects of airway pathology.
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Namvar
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Warn
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Farnell
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bromley
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Fraczek
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Bowyer
authors.affiliation: Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Herrick
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000946:Antigens, Fungal / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020397:Goblet Cells / Q000473:pathology; D006965:Hyperplasia; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010447:Peptide Hydrolases / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D000946:Antigens, Fungal; D003094:Collagen; D010447:Peptide Hydrolases
keywords: Aspergillus; Aspergillus fumigatus; Asthma; airway remodelling; alkaline serine protease; allergen; allergic; murine model