PB1-F2 Proteins from H5N1 and 20th Century Pandemic Influenza Viruses Cause Immunopathology

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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 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. There is presently great interest in understanding how influenza viruses cause disease. In this paper, we explore the role of the influenza virus PB1-F2 protein in disease. We show that the ability of the protein to cause cell death is mediated through a mitochondrial death pathway controlled by proteins called BAX or BAK. However, this function of the protein only seems to be relevant to a restricted set of viruses and not past pandemic strains. Instead, the ability to generate inflammation in the lung proves to be a common trait of all past pandemic strains as well as the H5N1 highly pathogenic avian influenza strains which remain a significant pandemic threat. It appears likely that this pro-inflammatory phenotype is a characteristic of viruses emerging from the avian reservoir and is therefore important for new strains that cross the species barrier and establish themselves in humans. During circulation and adaptation in the mammalian lung, this function is typically lost. Of note, the novel 2009 H1N1 pandemic strain does not express a full-length PB1-F2. Were it to acquire a fully functional, inflammatory PB1-F2 through reassortment, this could herald greatly enhanced disease potential.