Abstract
The proapoptotic PB1-F2 protein of influenza A viruses has been shown to contribute to pathogenesis in the mouse model. Expression of full-length PB1-F2 increases the pathogenesis of the influenza A virus, causing weight loss, slower viral clearance, and increased viral titers in the lungs. After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus. Two isogenic recombinant chimeric viruses were created with an influenza A/WSN/33 virus background containing the PB1 segment from the HK/156/97: WH and WH N66S. In mice infected with WH N66S virus there was increased pathogenicity as measured by weight loss and decreased survival, and a 100-fold increase in virus replication when compared to mice infected with the WH virus. The 1918 pandemic strain A/Brevig Mission/18 was reconstructed with a pathogenicity-reducing mutation in PB1-F2 (S66N). The resultant 1918 S66N virus was attenuated in mice having a 3-log lower 50% lethal dose and caused less morbidity and mortality in mice than the wild-type virus. Viral lung titers were also decreased in 1918 S66N–infected mice compared with wild-type 1918 virus–infected mice. In addition, both viruses with an S at position 66 (WH N66S and wt 1918) induced elevated levels of cytokines in the lungs of infected mice. Together, these data show that a single amino acid substitution in PB1-F2 can result in increased viral pathogenicity and could be one of the factors contributing to the high lethality seen with the 1918 pandemic virus.
Highlights
Influenza A virus causes 300,000–500,000 deaths worldwide each year, and in pandemic years, this number can increase to 1 million or as high as 50 million, as was seen in 1918–1919 [1,2,3]
It has been previously shown that PB1-F2 is present in the mitochondria, where it induces cell death; our laboratory has demonstrated that PB1-F2 is a contributor to pathogenesis in the mouse model of infection
To study PB1-F2 further, we examined highly pathogenic strains of avian influenza virus and located an amino acid change that seemed to be associated with increased death in mice
Summary
Influenza A virus causes 300,000–500,000 deaths worldwide each year, and in pandemic years, this number can increase to 1 million (in 1957–1958 ) or as high as 50 million, as was seen in 1918–1919 [1,2,3]. H5N1 infections in humans were seen in Hong Kong in a small outbreak in 1997 that resulted in 18 human infections and six fatalities, and since 2003, 309 human cases of H5N1 have been confirmed with a 61% fatality rate (6/1/07) [4,5,6,7] Recent work on these viruses has aimed to elucidate the virulence factors that account for the severe illness observed in humans and mice [4,8,9,10,11,12]. Recent identification and characterization of a novel influenza virus protein called PB1-F2 encoded by the PB1 gene introduced a potential virulence factor that could play a role in pathogenesis of infection with pandemic influenza viruses and explain the selection of the PB1 gene in these viruses [17]
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