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

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 20th 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. © 2010 mcauley et al.