title: PB1-F2 proteins from H5N1 and 20 century pandemic influenza viruses cause immunopathology.
abstract: 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.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Julie L
authors.initials: JL
authors.lastname: McAuley
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Chipuk
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: Nick
authors.initials: N
authors.lastname: Van De Velde
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
mesh_terms: D000818:Animals; D001717:Birds; D004196:Disease Outbreaks / Q000266:history; D049673:History, 20th Century; D006801:Humans; D007107:Immune System / Q000473:pathology / Q000821:virology*; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000276:immunology / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000821:virology; D007251:Influenza, Human / Q000821:virology; D009975:Orthomyxoviridae; D014764:Viral Proteins / Q000502:physiology*
chemical_list: C442816:PB1-F2 protein, Influenza A virus; D014764:Viral Proteins