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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 sequences of viruses used in this study.A comparison of the predicted amino acid sequences of the C-terminal regions of PB1-F2 proteins of several epidemiologically important strains is presented. Colored lines at the bottom of the Figure represent the amino acid composition of the predicted helical region (blue), the 27-mer peptides used in this study (green), and the predicted mitochondrial targeting sequence (red). Blue shading highlights differences in predicted amino acid sequence between the seasonal (1995) and pandemic (1968) H3N2 strains. Yellow shading indicates amino acids predicted to be involved in the cell death phenotype of PR8 (see discussion). Green shading highlights the N66S mutation, a predicted virulence determinant for the 1918 pandemic strain [13].
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ppat-1001014-g001: PB1-F2 sequences of viruses used in this study.A comparison of the predicted amino acid sequences of the C-terminal regions of PB1-F2 proteins of several epidemiologically important strains is presented. Colored lines at the bottom of the Figure represent the amino acid composition of the predicted helical region (blue), the 27-mer peptides used in this study (green), and the predicted mitochondrial targeting sequence (red). Blue shading highlights differences in predicted amino acid sequence between the seasonal (1995) and pandemic (1968) H3N2 strains. Yellow shading indicates amino acids predicted to be involved in the cell death phenotype of PR8 (see discussion). Green shading highlights the N66S mutation, a predicted virulence determinant for the 1918 pandemic strain [13].

Mentions: Peptides derived from PB1-F2 C-terminal sequences of PR8, the three 20th century pandemic strains (1918, 1957, 1968), a recent highly pathogenic avian influenza virus of the H5N1 subtype, and a recent seasonal H3N2 strain were synthesized for study [10], [15] (Figure 1). Recent seasonal H1N1 strains express a form of PB1-F2 truncated after 57 amino acids, lacking the mitochondrial targeting sequence located in the C-terminal region, and thus could not be evaluated in this manner [15], [16]. The predicted secondary structures of these peptides were determined by circular dichroism and match the reported structure of this region as described for full-length protein and 44-mer peptides [17], [18] (data not shown). These peptides are internalized when presented to cells in vitro, and are observed to have similar intracellular distributions and kinetics of degradation as does full length protein expressed from the virus (Figure S1; Text S1).


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 sequences of viruses used in this study.A comparison of the predicted amino acid sequences of the C-terminal regions of PB1-F2 proteins of several epidemiologically important strains is presented. Colored lines at the bottom of the Figure represent the amino acid composition of the predicted helical region (blue), the 27-mer peptides used in this study (green), and the predicted mitochondrial targeting sequence (red). Blue shading highlights differences in predicted amino acid sequence between the seasonal (1995) and pandemic (1968) H3N2 strains. Yellow shading indicates amino acids predicted to be involved in the cell death phenotype of PR8 (see discussion). Green shading highlights the N66S mutation, a predicted virulence determinant for the 1918 pandemic strain [13].
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001014-g001: PB1-F2 sequences of viruses used in this study.A comparison of the predicted amino acid sequences of the C-terminal regions of PB1-F2 proteins of several epidemiologically important strains is presented. Colored lines at the bottom of the Figure represent the amino acid composition of the predicted helical region (blue), the 27-mer peptides used in this study (green), and the predicted mitochondrial targeting sequence (red). Blue shading highlights differences in predicted amino acid sequence between the seasonal (1995) and pandemic (1968) H3N2 strains. Yellow shading indicates amino acids predicted to be involved in the cell death phenotype of PR8 (see discussion). Green shading highlights the N66S mutation, a predicted virulence determinant for the 1918 pandemic strain [13].
Mentions: Peptides derived from PB1-F2 C-terminal sequences of PR8, the three 20th century pandemic strains (1918, 1957, 1968), a recent highly pathogenic avian influenza virus of the H5N1 subtype, and a recent seasonal H3N2 strain were synthesized for study [10], [15] (Figure 1). Recent seasonal H1N1 strains express a form of PB1-F2 truncated after 57 amino acids, lacking the mitochondrial targeting sequence located in the C-terminal region, and thus could not be evaluated in this manner [15], [16]. The predicted secondary structures of these peptides were determined by circular dichroism and match the reported structure of this region as described for full-length protein and 44-mer peptides [17], [18] (data not shown). These peptides are internalized when presented to cells in vitro, and are observed to have similar intracellular distributions and kinetics of degradation as does full length protein expressed from the virus (Figure S1; Text S1).

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