title: Combined Haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma.
abstract: BACKGROUND
  20-30% of patients with asthma have neutrophilic airway inflammation and reduced responsiveness to steroid therapy. They often have chronic airway bacterial colonisation and Haemophilus influenzae is one of the most commonly isolated bacteria. The relationship between chronic airway colonisation and the development of steroid-resistant neutrophilic asthma is unclear.
  
  
  OBJECTIVE
  To investigate the relationship between H influenzae respiratory infection and neutrophilic asthma using mouse models of infection and ovalbumin (OVA)-induced allergic airways disease.
  
  
  METHODS
  BALB/c mice were intratracheally infected with H influenzae (day 10), intraperitoneally sensitised (day 0) and intranasally challenged (day 12-15) with OVA. Treatment groups were administered dexamethasone intranasally during OVA challenge. Infection, allergic airways disease, steroid sensitivity and immune responses were assessed (days 11, 16 and 21).
  
  
  RESULTS
  The combination of H influenzae infection and allergic airways disease resulted in chronic lung infection that was detected on days 11, 16 and 21 (21, 26 and 31 days after infection). Neutrophilic allergic airways disease and T helper 17 cell development were induced, which did not require active infection. Importantly, all features of neutrophilic allergic airways disease were steroid resistant. Toll-like receptor 4 expression and activation of phagocytes was reduced, but most significantly the influx and/or development of phagocytosing neutrophils and macrophages into the airways was inhibited.
  
  
  CONCLUSIONS
  The combination of infection and allergic airways disease promotes bacterial persistence, leading to the development of a phenotype similar to steroid-resistant neutrophilic asthma and which may result from dysfunction in innate immune cells. This indicates that targeting bacterial infection in steroid-resistant asthma may have therapeutic benefit.
authors.affiliation: Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
authors.forename: Ama-Tawiah
authors.initials: AT
authors.lastname: Essilfie
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Simpson
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Dunkley
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Morgan
authors.forename: Brian G
authors.initials: BG
authors.lastname: Oliver
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D006192:Haemophilus Infections / Q000150:complications* / Q000276:immunology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000472:pathogenicity*; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D051197:Toll-Like Receptor 4