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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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Related in: MedlinePlus

PB1-F2 contributes to influenza virus mediated immunopathology.Groups of mice were infected with a panel of viruses as indicated (see methods for definitions) and euthanized 72 hours post-infection. Lungs were removed, sufflated, sectioned, and examined for histopathology following A) staining with hematoxylin and eosin or B) application of an antibody specific for MPO followed by a horse-radish peroxidase-conjugated secondary antibody, staining with chromagen DAB, and counterstaining with hematoxylin.
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ppat-1001014-g007: PB1-F2 contributes to influenza virus mediated immunopathology.Groups of mice were infected with a panel of viruses as indicated (see methods for definitions) and euthanized 72 hours post-infection. Lungs were removed, sufflated, sectioned, and examined for histopathology following A) staining with hematoxylin and eosin or B) application of an antibody specific for MPO followed by a horse-radish peroxidase-conjugated secondary antibody, staining with chromagen DAB, and counterstaining with hematoxylin.

Mentions: To assess this inflammatory phenotype in the context of a full virus, mice were infected with WT PR8, 1918 PB1-F2/PR8, ΔPB1-F2/PR8, or Beij PB1-F2/PR8 and were euthanized 72 hours later for histopathologic examination as described above. In all lungs examined, pathologic changes typical of PR8 viral infection were observed, including perivascular infiltration of lymphocytes into interstitial regions, areas of focal necrosis of terminal airways and prominent cellular debris associated with acute hemorrhage into alveoli (Figure 7A). In the lungs of mice infected with PR8 or 1918 PB1-F2/PR8, however, significantly more perivascular cuffing was noted, consisting of an admixture of both viable and degenerate neutrophils and macrophages. The number of inflammatory cells seen in both the interstitium and alveoli was noticeably greater in these mice than in mice infected with ΔPB1-F2/PR8 or Beij PB1-F2/PR8. This finding supports the BAL data presented in Figure 5 and the histopathologic changes caused by the PB1-F2 peptide alone in Figure 6. Staining for myeloperoxidase (MPO) highlighted the influx of granulocytes and resulting inflammation in the lungs of mice infected with PR8 or 1918 PB1-F2/PR8 and was significantly more intense in these lungs compared to the ΔPB1-F2/PR8 or Beij PB1-F2/PR8 infected lungs (Figure 7B). We conclude that expression of full length PB1-F2 enhances lung inflammation during influenza virus pneumonia and increases the pathologic damage that occurs. During infections with viruses such as PR8 that are capable of causing PB1-F2 mediated cell death and inflammation by an unrelated mechanism, the lung injury is enhanced.


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 contributes to influenza virus mediated immunopathology.Groups of mice were infected with a panel of viruses as indicated (see methods for definitions) and euthanized 72 hours post-infection. Lungs were removed, sufflated, sectioned, and examined for histopathology following A) staining with hematoxylin and eosin or B) application of an antibody specific for MPO followed by a horse-radish peroxidase-conjugated secondary antibody, staining with chromagen DAB, and counterstaining with hematoxylin.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908617&req=5

ppat-1001014-g007: PB1-F2 contributes to influenza virus mediated immunopathology.Groups of mice were infected with a panel of viruses as indicated (see methods for definitions) and euthanized 72 hours post-infection. Lungs were removed, sufflated, sectioned, and examined for histopathology following A) staining with hematoxylin and eosin or B) application of an antibody specific for MPO followed by a horse-radish peroxidase-conjugated secondary antibody, staining with chromagen DAB, and counterstaining with hematoxylin.
Mentions: To assess this inflammatory phenotype in the context of a full virus, mice were infected with WT PR8, 1918 PB1-F2/PR8, ΔPB1-F2/PR8, or Beij PB1-F2/PR8 and were euthanized 72 hours later for histopathologic examination as described above. In all lungs examined, pathologic changes typical of PR8 viral infection were observed, including perivascular infiltration of lymphocytes into interstitial regions, areas of focal necrosis of terminal airways and prominent cellular debris associated with acute hemorrhage into alveoli (Figure 7A). In the lungs of mice infected with PR8 or 1918 PB1-F2/PR8, however, significantly more perivascular cuffing was noted, consisting of an admixture of both viable and degenerate neutrophils and macrophages. The number of inflammatory cells seen in both the interstitium and alveoli was noticeably greater in these mice than in mice infected with ΔPB1-F2/PR8 or Beij PB1-F2/PR8. This finding supports the BAL data presented in Figure 5 and the histopathologic changes caused by the PB1-F2 peptide alone in Figure 6. Staining for myeloperoxidase (MPO) highlighted the influx of granulocytes and resulting inflammation in the lungs of mice infected with PR8 or 1918 PB1-F2/PR8 and was significantly more intense in these lungs compared to the ΔPB1-F2/PR8 or Beij PB1-F2/PR8 infected lungs (Figure 7B). We conclude that expression of full length PB1-F2 enhances lung inflammation during influenza virus pneumonia and increases the pathologic damage that occurs. During infections with viruses such as PR8 that are capable of causing PB1-F2 mediated cell death and inflammation by an unrelated mechanism, the lung injury is enhanced.

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