title: An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model.
abstract: BACKGROUND
  Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics.
  
  
  OBJECTIVE
  We developed and characterized a robust, consistent, and reproducible mouse model of severe exacerbation of chronic allergic asthma.
  
  
  METHODS
  Chronic allergic airway inflammation was induced following a house dust mite (HDM) sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled fluticasone propionate (FP), systemic corticosteroids (Pred), or anti-IL-5. Mice were killed at different time points after infection: Cellular accumulation and cytokines levels in the airways, PenH as a measure of airway hyper-responsiveness (AHR), and lung histology and viral replication were assessed.
  
  
  RESULTS
  Infection with low-dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial, and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14 h after virus exposure by a marked innate, but no Th2 and Th1 response subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic, and T cells into the lung lumen, parenchyma, and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation.
  
  
  CONCLUSIONS
  Together, these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote the development of novel therapeutics.
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.|Department of Respiratory Medicine, Academic Medical Centre.
authors.forename: L
authors.initials: L
authors.lastname: Ravanetti
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.|Department of Respiratory Medicine, Academic Medical Centre.
authors.forename: A
authors.initials: A
authors.lastname: Dijkhuis
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.|Department of Respiratory Medicine, Academic Medical Centre.
authors.forename: Y S
authors.initials: YS
authors.lastname: Sabogal Pineros
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Bal
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.
authors.forename: B S
authors.initials: BS
authors.lastname: Dierdorp
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.
authors.forename: T
authors.initials: T
authors.lastname: Dekker
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.
authors.forename: A
authors.initials: A
authors.lastname: Logiantara
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, Royal Brompton Campus, London, UK.
authors.forename: I M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Immunology Discovery, Janssen Research and Development LLC, San Diego, CA, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Rao
authors.affiliation: Bioceros, Utrecht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Boon
authors.affiliation: Pulmonary Pharmacology Unit, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Villetti
authors.affiliation: Department of Respiratory Medicine, Academic Medical Centre.
authors.forename: P J
authors.initials: PJ
authors.lastname: Sterk
authors.affiliation: Pulmonary Pharmacology Unit, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre.|Department of Respiratory Medicine, Academic Medical Centre.
authors.forename: R
authors.initials: R
authors.lastname: Lutter
mesh_terms: D000485:Allergens / Q000276:immunology; D066258:Amphiregulin / Q000096:biosynthesis; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D001706:Biopsy; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D004361:Drug Tolerance; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D000068298:Fluticasone / Q000494:pharmacology; D007113:Immunity, Innate; D007114:Immunization; D009980:Influenza A virus; D015848:Interleukin-5 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000821:virology; D039981:Pyroglyphidae / Q000276:immunology; D013256:Steroids / Q000494:pharmacology*; D019562:Viral Load
chemical_list: D000485:Allergens; D066258:Amphiregulin; D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D016207:Cytokines; D015848:Interleukin-5; D013256:Steroids; D000068298:Fluticasone
keywords: animal models; asthma; basic immunology; innate immunity; virus