title: Heterozygosity for the F508del mutation in the cystic fibrosis transmembrane conductance regulator anion channel attenuates influenza severity.
abstract: BACKGROUND
  Seasonal and pandemic influenza are significant public health concerns. Influenza stimulates respiratory epithelial Cl(-) secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of this study was to determine the contribution of this effect to influenza pathogenesis in mice with reduced CFTR activity.
  
  
  METHODS
  C57BL/6-congenic mice heterozygous for the F508del CFTR mutation (HET) and wild-type (WT) controls were infected intranasally with 10 000 focus-forming units of influenza A/WSN/33 (H1N1) per mouse. Body weight, arterial O2 saturation, and heart rate were monitored daily. Pulmonary edema and lung function parameters were derived from ratios of wet weight to dry weight and the forced-oscillation technique, respectively. Levels of cytokines and chemokines in bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Relative to WT mice, influenza virus-infected HET mice showed significantly delayed mortality, which was accompanied by attenuated hypoxemia, cardiopulmonary dysfunction, and pulmonary edema. However, viral replication and weight loss did not differ. The protective HET phenotype was correlated with exaggerated alveolar macrophage and interleukin 6 responses to infection and was abrogated by alveolar macrophage depletion, using clodronate liposomes.
  
  
  CONCLUSIONS
  Reduced CFTR expression modulates the innate immune response to influenza and alters disease pathogenesis. CFTR-mediated Cl(-) secretion is therefore an important host determinant of disease, and CFTR inhibition may be of therapeutic benefit in influenza.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Famke
authors.initials: F
authors.lastname: Aeffner
authors.forename: Basant
authors.initials: B
authors.lastname: Abdulrahman
authors.forename: Judy M
authors.initials: JM
authors.lastname: Hickman-Davis
authors.forename: Paul M
authors.initials: PM
authors.lastname: Janssen
authors.forename: Amal
authors.initials: A
authors.lastname: Amer
authors.forename: David M
authors.initials: DM
authors.lastname: Bedwell
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006579:Heterozygote; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009975:Orthomyxoviridae; D009976:Orthomyxoviridae Infections / Q000235:genetics* / Q000473:pathology*; D017384:Sequence Deletion
chemical_list: D016207:Cytokines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; Influenza; alveolar macrophage; cystic fibrosis; hypoxemia; lung function; pulmonary edema