PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology

PLoS Pathog. 2010 Jul 22;6(7):e1001014. doi: 10.1371/journal.ppat.1001014.


With the recent emergence of a novel pandemic strain, there is presently intense interest in understanding the molecular signatures of virulence of influenza viruses. PB1-F2 proteins from epidemiologically important influenza A virus strains were studied to determine their function and contribution to virulence. Using 27-mer peptides derived from the C-terminal sequence of PB1-F2 and chimeric viruses engineered on a common background, we demonstrated that induction of cell death through PB1-F2 is dependent upon BAK/BAX mediated cytochrome c release from mitochondria. This function was specific for the PB1-F2 protein of A/Puerto Rico/8/34 and was not seen using PB1-F2 peptides derived from past pandemic strains. However, PB1-F2 proteins from the three pandemic strains of the 20(th) century and a highly pathogenic strain of the H5N1 subtype were shown to enhance the lung inflammatory response resulting in increased pathology. Recently circulating seasonal influenza A strains were not capable of this pro-inflammatory function, having lost the PB1-F2 protein's immunostimulatory activity through truncation or mutation during adaptation in humans. These data suggest that the PB1-F2 protein contributes to the virulence of pandemic strains when the PB1 gene segment is recently derived from the avian reservoir.

Publication types

  • Historical Article
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Birds
  • Disease Outbreaks / history
  • History, 20th Century
  • Humans
  • Immune System / pathology
  • Immune System / virology*
  • Influenza A Virus, H5N1 Subtype / chemistry
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza A Virus, H5N1 Subtype / pathogenicity*
  • Influenza in Birds / virology
  • Influenza, Human / virology
  • Orthomyxoviridae
  • Viral Proteins / physiology*


  • PB1-F2 protein, Influenza A virus
  • Viral Proteins