title: Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice.
abstract: During the 2009 H1N1 influenza pandemic, infection attack rates were particularly high among young individuals who suffered from pneumonia with occasional death. Moreover, previously reported determinants of mammalian adaptation and pathogenicity were not present in 2009 pandemic H1N1 influenza A viruses. Thus, it was proposed that unknown viral factors might have contributed to disease severity in humans. In this study, we performed a comparative analysis of two clinical 2009 pandemic H1N1 strains that belong to the very early and later phases of the pandemic. We identified mutations in the viral hemagglutinin (HA) and the nucleoprotein (NP) that occurred during pandemic progression and mediate increased virulence in mice. Lethal disease outcome correlated with elevated viral replication in the alveolar epithelium, increased proinflammatory cytokine and chemokine responses, pneumonia, and lymphopenia in mice. These findings show that viral mutations that have occurred during pandemic circulation among humans are associated with severe disease in mice.
  
  
  OBJECTIVE
  In this study, novel determinants of 2009 pandemic H1N1 influenza pathogenicity were identified in the viral hemagglutinin (HA) and the nucleoprotein (NP) genes. In contrast to highly pathogenic avian influenza viruses, increased virulence in mice did not correlate with enhanced polymerase activity but with reduced activity. Lethal 2009 pandemic H1N1 infection in mice correlated with lymphopenia and severe pneumonia. These studies suggest that molecular mechanisms that mediate 2009 pandemic H1N1 influenza pathogenicity are distinct from those that mediate avian influenza virus pathogenicity in mice.
authors.affiliation: Viral Zoonoses and Adaptation Research Group, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Otte
authors.affiliation: Department for Molecular Pathology, Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sauter
authors.affiliation: Department for Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Daxer
authors.affiliation: Department for Algorithmic Bioinformatics, Heinrich Heine University, Düsseldorf, Germany Department for Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: McHardy
authors.affiliation: Department for Molecular Pathology, Institute of Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Klingel
authors.affiliation: Viral Zoonoses and Adaptation Research Group, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany guelsah.gabriel@hpi.uni-hamburg.de.
authors.forename: G
authors.initials: G
authors.lastname: Gabriel
mesh_terms: D000818:Animals; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000821:virology; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006651:Histocytochemistry; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology*; D007251:Influenza, Human / Q000821:virology*; D008231:Lymphopenia; D008810:Mice, Inbred C57BL; D009154:Mutation; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology*; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics; D020545:Respiratory Mucosa / Q000821:virology; D014758:Viral Core Proteins / Q000235:genetics; D014774:Virulence; D014779:Virus Replication
chemical_list: D016207:Cytokines; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins