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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 derived peptides cause inflammation and lung pathology.Groups of mice were exposed to a panel of peptides (100 mM final concentration, see Figure 1 for definitions) and euthanized 72 hours later. Lungs were removed, sufflated, sectioned, and stained with hematoxylin and eosin for histopathologic evaluation. Representative 40× sections are shown from mice exposed to peptides derived from the PB1-F2 protein of A) PR8, B) H1N1 1918, C) H2N2 1957, D) H5N1 2004, E) H3N2 1995, or F) no peptide control.
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ppat-1001014-g006: PB1-F2 derived peptides cause inflammation and lung pathology.Groups of mice were exposed to a panel of peptides (100 mM final concentration, see Figure 1 for definitions) and euthanized 72 hours later. Lungs were removed, sufflated, sectioned, and stained with hematoxylin and eosin for histopathologic evaluation. Representative 40× sections are shown from mice exposed to peptides derived from the PB1-F2 protein of A) PR8, B) H1N1 1918, C) H2N2 1957, D) H5N1 2004, E) H3N2 1995, or F) no peptide control.

Mentions: Having determined that PB1-F2 drives an influx of inflammatory cells into the lungs that is detectable in BAL fluid, we next assessed the impact of this enhanced inflammatory response on histopathologic changes in lung tissue. Groups of mice were exposed to the panel of peptides and euthanized 24 or 72 hours later for examination of the lungs by an experienced veterinary pathologist (K.L.B.) who was blinded to the purpose of the study and the composition of the groups. At the 24 hour timepoint, only minimal perivascular changes were observed and no differences were apparent between groups (data not shown). 72 hours after exposure, however, significant pathology was observed in some groups of mice compared to others, mirroring the dichotomy in morbidity pictured in Figure 4C. Only minimal rare, perivascular infiltration of lymphocytes around small vessels was observed in mice exposed to the N-terminal control peptide or the peptide derived from the H3N2 seasonal strain A/Wuhan/359/1995 (Figure 6E, F). However, in mice exposed to peptides derived from the pandemic strains from 1918 and 1957, as well as the peptide from a 2004 H5N1 strain, hypertrophy of type II pneumocytes and thickening of alveolar septae were observed. Significant infiltration of neutrophils and macrophages was noted in both interstitial perivascular regions as well as within alveolar spaces (Figure 6B–D). Macrophages grossly outnumbered neutrophils, mirroring the findings in BAL fluid following peptide exposure (Figure 4A, B).


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 derived peptides cause inflammation and lung pathology.Groups of mice were exposed to a panel of peptides (100 mM final concentration, see Figure 1 for definitions) and euthanized 72 hours later. Lungs were removed, sufflated, sectioned, and stained with hematoxylin and eosin for histopathologic evaluation. Representative 40× sections are shown from mice exposed to peptides derived from the PB1-F2 protein of A) PR8, B) H1N1 1918, C) H2N2 1957, D) H5N1 2004, E) H3N2 1995, or F) no peptide control.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1001014-g006: PB1-F2 derived peptides cause inflammation and lung pathology.Groups of mice were exposed to a panel of peptides (100 mM final concentration, see Figure 1 for definitions) and euthanized 72 hours later. Lungs were removed, sufflated, sectioned, and stained with hematoxylin and eosin for histopathologic evaluation. Representative 40× sections are shown from mice exposed to peptides derived from the PB1-F2 protein of A) PR8, B) H1N1 1918, C) H2N2 1957, D) H5N1 2004, E) H3N2 1995, or F) no peptide control.
Mentions: Having determined that PB1-F2 drives an influx of inflammatory cells into the lungs that is detectable in BAL fluid, we next assessed the impact of this enhanced inflammatory response on histopathologic changes in lung tissue. Groups of mice were exposed to the panel of peptides and euthanized 24 or 72 hours later for examination of the lungs by an experienced veterinary pathologist (K.L.B.) who was blinded to the purpose of the study and the composition of the groups. At the 24 hour timepoint, only minimal perivascular changes were observed and no differences were apparent between groups (data not shown). 72 hours after exposure, however, significant pathology was observed in some groups of mice compared to others, mirroring the dichotomy in morbidity pictured in Figure 4C. Only minimal rare, perivascular infiltration of lymphocytes around small vessels was observed in mice exposed to the N-terminal control peptide or the peptide derived from the H3N2 seasonal strain A/Wuhan/359/1995 (Figure 6E, F). However, in mice exposed to peptides derived from the pandemic strains from 1918 and 1957, as well as the peptide from a 2004 H5N1 strain, hypertrophy of type II pneumocytes and thickening of alveolar septae were observed. Significant infiltration of neutrophils and macrophages was noted in both interstitial perivascular regions as well as within alveolar spaces (Figure 6B–D). Macrophages grossly outnumbered neutrophils, mirroring the findings in BAL fluid following peptide exposure (Figure 4A, B).

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