title: Nonstructural protein 1 (NS1)-mediated inhibition of c-Abl results in acute lung injury and priming for bacterial co-infections: insights into 1918 H1N1 pandemic?
abstract: BACKGROUND
  Nonstructural protein 1 (NS1) proteins from avian influenza viruses like the 1918 pandemic NS1 are capable of inhibiting the key signaling integrator c-Abl (Abl1), resulting in massive cytopathic cell alterations.
  
  
  METHODS
  In the current study, we addressed the consequences of NS1-mediated alteration of c-Abl on acute lung injury and pathogenicity in an in vivo mouse model.
  
  
  RESULTS
  Comparing isogenic strains that differ only in their ability to inhibit c-Abl, we observed elevated pathogenicity for the c-Abl-inhibiting virus. NS1-mediated blockade of c-Abl resulted in severe lung pathology and massive edema formation and facilitated secondary bacterial pneumonia. This phenotype was independent of differences in replication and immune responses, defining it as an NS1 virulence mechanism distinct from its canonical functions. Microarray analysis revealed extensive downregulation of genes involved in cell integrity and vascular endothelial regulation.
  
  
  CONCLUSIONS
  NS1 protein-mediated blockade of c-Abl signaling drives acute lung injury and primes for bacterial coinfections revealing potential insights into the pathogenicity of the 1918 pandemic virus.
authors.affiliation: Department of Infectious Diseases.
authors.forename: Eike R
authors.initials: ER
authors.lastname: Hrincius
authors.affiliation: Institute of Molecular Virology, University of Muenster, Germany.
authors.forename: Swantje
authors.initials: S
authors.lastname: Liedmann
authors.affiliation: Department of Computational Biology.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Department of Veterinary Pathology, St Jude Children's Research Hospital.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Infectious Diseases.
authors.forename: Shane
authors.initials: S
authors.lastname: Gansebom
authors.affiliation: Institute of Molecular Virology, University of Muenster, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ehrhardt
authors.affiliation: Institute of Molecular Virology, University of Muenster, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.affiliation: Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis.
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
authors.affiliation: Department of Infectious Diseases.
authors.forename: Richard
authors.initials: R
authors.lastname: Webby
authors.affiliation: Department of Infectious Diseases Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
mesh_terms: D055371:Acute Lung Injury / Q000150:complications / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001424:Bacterial Infections / Q000209:etiology*; D015415:Biomarkers; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D064149:Influenza Pandemic, 1918-1919; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000821:virology*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D016315:Proto-Oncogene Proteins c-abl
keywords: Influenza A virus; NS1 protein; acute lung injury; bacterial coinfections; c-Abl