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

McAuley JL, Chipuk JE, Boyd KL, Van De Velde N, Green DR, McCullers JA - PLoS Pathog. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

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.

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PB1-F2 enhances viral-mediated lung inflammation.Groups of mice were infected with a panel of viruses (see methods for definitions) and euthanized 72 hours post-infection. BAL fluid from the animals was assayed by flow-cytometry [10] for the mean number of A) white blood cells, B) macrophages, and C) neutrophils compared to uninfected mice or mice infected with a virus lacking the ability to express PB1-F2. An asterisk (*) indicates a significant difference compared to animals infected with the ΔPB1-F2/PR8 or Beij PB1-F2/PR8 viruses, and uninfected control animals by ANOVA (p<0.05). A double asterisk (**) indicates a significant difference compared to animals infected with the Beij PB1-F2/PR8 virus and uninfected control animals. A triple asterisk (***) indicates a significant difference compared to animals infected with the H5N1 ΔPB1-F2/PR8 virus and uninfected control animals. Error bars indicate the standard deviation from the mean.
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ppat-1001014-g005: PB1-F2 enhances viral-mediated lung inflammation.Groups of mice were infected with a panel of viruses (see methods for definitions) and euthanized 72 hours post-infection. BAL fluid from the animals was assayed by flow-cytometry [10] for the mean number of A) white blood cells, B) macrophages, and C) neutrophils compared to uninfected mice or mice infected with a virus lacking the ability to express PB1-F2. An asterisk (*) indicates a significant difference compared to animals infected with the ΔPB1-F2/PR8 or Beij PB1-F2/PR8 viruses, and uninfected control animals by ANOVA (p<0.05). A double asterisk (**) indicates a significant difference compared to animals infected with the Beij PB1-F2/PR8 virus and uninfected control animals. A triple asterisk (***) indicates a significant difference compared to animals infected with the H5N1 ΔPB1-F2/PR8 virus and uninfected control animals. Error bars indicate the standard deviation from the mean.

Mentions: To assess the contribution of PB1-F2 to inflammation in the context of a full virus, where expression of other proteins is likely to contribute to the inflammatory response, we utilized the previously described set of viruses on the PR8 backbone in a mouse infection model. In data previously reported with these viruses, alteration or abrogation of PB1-F2 did not result in significant differences in weight loss, in the dose needed to cause death in mice, or in viral lung titers 1, 3, 5 and 7 days after infection for any comparisons except those previously reported for the 1918 PB1-F2 [10], [15]. However, the differential effects of PB1-F2 expression could clearly be seen in the inflammatory response in the lungs. Disruption of PB1-F2 expression in PR8 or replacement of the PR8 PB1-F2 with the C-terminally truncated Beij PB1-F2 both significantly reduced the number of white blood cells found in BALF 3 days post viral infection (Figure 5A) compared to PR8. This significant difference was maintained when specifically assessing the influx of either macrophages or neutrophils (Figure 5B, C). Expression of the 1918 PB1-F2 led to effects similar to those of the PR8 virus. Use of the virus containing the H5N1 PB1 gene segment in a PR8 background revealed that disruption of PB1-F2 expression also significantly depressed the inflammatory response compared to the virus maintaining the ability to express full length PB1-F2 (Figure 5A, B, C). However, in agreement with the peptide data, no differences were seen that could be attributed to the 1995 H3N2 derived PB1-F2.


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

McAuley JL, Chipuk JE, Boyd KL, Van De Velde N, Green DR, McCullers JA - PLoS Pathog. (2010)

PB1-F2 enhances viral-mediated lung inflammation.Groups of mice were infected with a panel of viruses (see methods for definitions) and euthanized 72 hours post-infection. BAL fluid from the animals was assayed by flow-cytometry [10] for the mean number of A) white blood cells, B) macrophages, and C) neutrophils compared to uninfected mice or mice infected with a virus lacking the ability to express PB1-F2. An asterisk (*) indicates a significant difference compared to animals infected with the ΔPB1-F2/PR8 or Beij PB1-F2/PR8 viruses, and uninfected control animals by ANOVA (p<0.05). A double asterisk (**) indicates a significant difference compared to animals infected with the Beij PB1-F2/PR8 virus and uninfected control animals. A triple asterisk (***) indicates a significant difference compared to animals infected with the H5N1 ΔPB1-F2/PR8 virus and uninfected control animals. Error bars indicate the standard deviation from the mean.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2908617&req=5

ppat-1001014-g005: PB1-F2 enhances viral-mediated lung inflammation.Groups of mice were infected with a panel of viruses (see methods for definitions) and euthanized 72 hours post-infection. BAL fluid from the animals was assayed by flow-cytometry [10] for the mean number of A) white blood cells, B) macrophages, and C) neutrophils compared to uninfected mice or mice infected with a virus lacking the ability to express PB1-F2. An asterisk (*) indicates a significant difference compared to animals infected with the ΔPB1-F2/PR8 or Beij PB1-F2/PR8 viruses, and uninfected control animals by ANOVA (p<0.05). A double asterisk (**) indicates a significant difference compared to animals infected with the Beij PB1-F2/PR8 virus and uninfected control animals. A triple asterisk (***) indicates a significant difference compared to animals infected with the H5N1 ΔPB1-F2/PR8 virus and uninfected control animals. Error bars indicate the standard deviation from the mean.
Mentions: To assess the contribution of PB1-F2 to inflammation in the context of a full virus, where expression of other proteins is likely to contribute to the inflammatory response, we utilized the previously described set of viruses on the PR8 backbone in a mouse infection model. In data previously reported with these viruses, alteration or abrogation of PB1-F2 did not result in significant differences in weight loss, in the dose needed to cause death in mice, or in viral lung titers 1, 3, 5 and 7 days after infection for any comparisons except those previously reported for the 1918 PB1-F2 [10], [15]. However, the differential effects of PB1-F2 expression could clearly be seen in the inflammatory response in the lungs. Disruption of PB1-F2 expression in PR8 or replacement of the PR8 PB1-F2 with the C-terminally truncated Beij PB1-F2 both significantly reduced the number of white blood cells found in BALF 3 days post viral infection (Figure 5A) compared to PR8. This significant difference was maintained when specifically assessing the influx of either macrophages or neutrophils (Figure 5B, C). Expression of the 1918 PB1-F2 led to effects similar to those of the PR8 virus. Use of the virus containing the H5N1 PB1 gene segment in a PR8 background revealed that disruption of PB1-F2 expression also significantly depressed the inflammatory response compared to the virus maintaining the ability to express full length PB1-F2 (Figure 5A, B, C). However, in agreement with the peptide data, no differences were seen that could be attributed to the 1995 H3N2 derived PB1-F2.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

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.

Show MeSH
Related in: MedlinePlus