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Non-avian animal reservoirs present a source of influenza A PB1-F2 proteins with novel virulence-enhancing markers.

Alymova IV, York IA, McCullers JA - PLoS ONE (2014)

Bottom Line: Here, we analyze the frequency of virulence-associated residues in PB1-F2 sequences from IAVs circulating in mammalian species in close contact with humans: pigs, horses, and dogs.All four inflammatory residues were found in PB1-F2 proteins from these viruses.There is a need for surveillance of IAVs with genetic markers of virulence that may be emerging from these reservoirs in order to improve pandemic preparedness and response.

View Article: PubMed Central - PubMed

Affiliation: Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, United States of America; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

ABSTRACT
PB1-F2 protein, expressed from an alternative reading frame of most influenza A virus (IAV) PB1 segments, may possess specific residues associated with enhanced inflammation (L62, R75, R79, and L82) and cytotoxicity (I68, L69, and V70). These residues were shown to increase the pathogenicity of primary viral and secondary bacterial infections in a mouse model. In contrast to human seasonal influenza strains, virulence-associated residues are present in PB1-F2 proteins from pandemic H1N1 1918, H2N2 1957, and H3N2 1968, and highly pathogenic H5N1 strains, suggesting their contribution to viruses' pathogenic phenotypes. Non-human influenza strains may act as donors of virulent PB1-F2 proteins. Previously, avian influenza strains were identified as a potential source of inflammatory, but not cytotoxic, PB1-F2 residues. Here, we analyze the frequency of virulence-associated residues in PB1-F2 sequences from IAVs circulating in mammalian species in close contact with humans: pigs, horses, and dogs. All four inflammatory residues were found in PB1-F2 proteins from these viruses. Among cytotoxic residues, I68 was the most common and was especially prevalent in equine and canine IAVs. Historically, PB1-F2 from equine (about 75%) and canine (about 20%) IAVs were most likely to have combinations of the highest numbers of residues associated with inflammation and cytotoxicity, compared to about 7% of swine IAVs. Our analyses show that, in addition to birds, pigs, horses, and dogs are potentially important sources of pathogenic PB1-F2 variants. There is a need for surveillance of IAVs with genetic markers of virulence that may be emerging from these reservoirs in order to improve pandemic preparedness and response.

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Genetic markers of virulence in the PB1-F2 proteins from influenza viruses of domestic mammals.The IAV isolates of swine, horses, and dogs were categorized into the lineage (outer ring), PB1-F2 length (middle ring), and combination of inflammatory (indicated as “I”) and cytotoxic (indicated as “C”) residues (inner ring). Within the outer ring, the percentage of each grouping is shown relative to the total number of isolates. Within the middle and inner rings, the percentage of each grouping is shown relative to the preceding grouping. The numbers of inflammatory (indicated as “I1” through “I4”) and cytotoxic (indicated as “C1” and “C2”) residues were determined for PB1-F2 proteins with length of 62 or more amino acids (e.g. capable of encoding either inflammatory or cytotoxic residues).
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pone-0111603-g001: Genetic markers of virulence in the PB1-F2 proteins from influenza viruses of domestic mammals.The IAV isolates of swine, horses, and dogs were categorized into the lineage (outer ring), PB1-F2 length (middle ring), and combination of inflammatory (indicated as “I”) and cytotoxic (indicated as “C”) residues (inner ring). Within the outer ring, the percentage of each grouping is shown relative to the total number of isolates. Within the middle and inner rings, the percentage of each grouping is shown relative to the preceding grouping. The numbers of inflammatory (indicated as “I1” through “I4”) and cytotoxic (indicated as “C1” and “C2”) residues were determined for PB1-F2 proteins with length of 62 or more amino acids (e.g. capable of encoding either inflammatory or cytotoxic residues).

Mentions: Nucleotide sequences of PB1 proteins of well-established swine (H1N1, H1N2, and H3N2), equine (H7N7 and H3N8), and canine (H3N2 and H3N8) lineages existing in the NCBI (http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html) and GISAID (http://platform.gisaid.org; see Table S1 for acknowledgements) influenza virus resource databases were accessed on January 20, 2013. Rare viruses of other subtypes (e.g., H5N1 in swine or canine) were not included, as they generally represent cross-infection with avian viruses that do not persist and evolve in the new host. After removing duplicate strains and partial PB1 sequences that did not contain the PB1-F2 region, we analyzed 1647 swine (isolated from 1935–2012), 107 equine (1956–2011), and 82 canine (2003–2011) influenza viruses. The PB1-F2 regions from these sequences were translated and analyzed for the presence of the inflammatory (L62, R75, R79, and L82) and cytotoxic (I68, L79, and V70) residues (Figure 1). Next, sequences covering full-length PB1 were aligned using MAFFT [18] (excluding PB1 sequences that were identical at the nucleotide level to a sequence already included in the alignment), and phylogenetic trees (shown as an overview in figures 2 and 3, and as full text in Figures S1 and S2) were generated. Unrooted phylogenetic trees were constructed using maximum likelihood analysis with the nearest-neighbor-interchange method, based on the general time reversible model with gamma distributed rate heterogeneity with invariant site (G+I), implemented in MEGA 5.1 [19]. The reliability of the internal branches was evaluated using 500 bootstrap replicates; nodes supported at ≥80% are indicated in Figures S1 and S2.


Non-avian animal reservoirs present a source of influenza A PB1-F2 proteins with novel virulence-enhancing markers.

Alymova IV, York IA, McCullers JA - PLoS ONE (2014)

Genetic markers of virulence in the PB1-F2 proteins from influenza viruses of domestic mammals.The IAV isolates of swine, horses, and dogs were categorized into the lineage (outer ring), PB1-F2 length (middle ring), and combination of inflammatory (indicated as “I”) and cytotoxic (indicated as “C”) residues (inner ring). Within the outer ring, the percentage of each grouping is shown relative to the total number of isolates. Within the middle and inner rings, the percentage of each grouping is shown relative to the preceding grouping. The numbers of inflammatory (indicated as “I1” through “I4”) and cytotoxic (indicated as “C1” and “C2”) residues were determined for PB1-F2 proteins with length of 62 or more amino acids (e.g. capable of encoding either inflammatory or cytotoxic residues).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4219726&req=5

pone-0111603-g001: Genetic markers of virulence in the PB1-F2 proteins from influenza viruses of domestic mammals.The IAV isolates of swine, horses, and dogs were categorized into the lineage (outer ring), PB1-F2 length (middle ring), and combination of inflammatory (indicated as “I”) and cytotoxic (indicated as “C”) residues (inner ring). Within the outer ring, the percentage of each grouping is shown relative to the total number of isolates. Within the middle and inner rings, the percentage of each grouping is shown relative to the preceding grouping. The numbers of inflammatory (indicated as “I1” through “I4”) and cytotoxic (indicated as “C1” and “C2”) residues were determined for PB1-F2 proteins with length of 62 or more amino acids (e.g. capable of encoding either inflammatory or cytotoxic residues).
Mentions: Nucleotide sequences of PB1 proteins of well-established swine (H1N1, H1N2, and H3N2), equine (H7N7 and H3N8), and canine (H3N2 and H3N8) lineages existing in the NCBI (http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html) and GISAID (http://platform.gisaid.org; see Table S1 for acknowledgements) influenza virus resource databases were accessed on January 20, 2013. Rare viruses of other subtypes (e.g., H5N1 in swine or canine) were not included, as they generally represent cross-infection with avian viruses that do not persist and evolve in the new host. After removing duplicate strains and partial PB1 sequences that did not contain the PB1-F2 region, we analyzed 1647 swine (isolated from 1935–2012), 107 equine (1956–2011), and 82 canine (2003–2011) influenza viruses. The PB1-F2 regions from these sequences were translated and analyzed for the presence of the inflammatory (L62, R75, R79, and L82) and cytotoxic (I68, L79, and V70) residues (Figure 1). Next, sequences covering full-length PB1 were aligned using MAFFT [18] (excluding PB1 sequences that were identical at the nucleotide level to a sequence already included in the alignment), and phylogenetic trees (shown as an overview in figures 2 and 3, and as full text in Figures S1 and S2) were generated. Unrooted phylogenetic trees were constructed using maximum likelihood analysis with the nearest-neighbor-interchange method, based on the general time reversible model with gamma distributed rate heterogeneity with invariant site (G+I), implemented in MEGA 5.1 [19]. The reliability of the internal branches was evaluated using 500 bootstrap replicates; nodes supported at ≥80% are indicated in Figures S1 and S2.

Bottom Line: Here, we analyze the frequency of virulence-associated residues in PB1-F2 sequences from IAVs circulating in mammalian species in close contact with humans: pigs, horses, and dogs.All four inflammatory residues were found in PB1-F2 proteins from these viruses.There is a need for surveillance of IAVs with genetic markers of virulence that may be emerging from these reservoirs in order to improve pandemic preparedness and response.

View Article: PubMed Central - PubMed

Affiliation: Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, United States of America; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

ABSTRACT
PB1-F2 protein, expressed from an alternative reading frame of most influenza A virus (IAV) PB1 segments, may possess specific residues associated with enhanced inflammation (L62, R75, R79, and L82) and cytotoxicity (I68, L69, and V70). These residues were shown to increase the pathogenicity of primary viral and secondary bacterial infections in a mouse model. In contrast to human seasonal influenza strains, virulence-associated residues are present in PB1-F2 proteins from pandemic H1N1 1918, H2N2 1957, and H3N2 1968, and highly pathogenic H5N1 strains, suggesting their contribution to viruses' pathogenic phenotypes. Non-human influenza strains may act as donors of virulent PB1-F2 proteins. Previously, avian influenza strains were identified as a potential source of inflammatory, but not cytotoxic, PB1-F2 residues. Here, we analyze the frequency of virulence-associated residues in PB1-F2 sequences from IAVs circulating in mammalian species in close contact with humans: pigs, horses, and dogs. All four inflammatory residues were found in PB1-F2 proteins from these viruses. Among cytotoxic residues, I68 was the most common and was especially prevalent in equine and canine IAVs. Historically, PB1-F2 from equine (about 75%) and canine (about 20%) IAVs were most likely to have combinations of the highest numbers of residues associated with inflammation and cytotoxicity, compared to about 7% of swine IAVs. Our analyses show that, in addition to birds, pigs, horses, and dogs are potentially important sources of pathogenic PB1-F2 variants. There is a need for surveillance of IAVs with genetic markers of virulence that may be emerging from these reservoirs in order to improve pandemic preparedness and response.

Show MeSH
Related in: MedlinePlus