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A complete map of potential pathogenicity markers of avian influenza virus subtype H5 predicted from 11 expressed proteins.

Khaliq Z, Leijon M, Belák S, Komorowski J - BMC Microbiol. (2015)

Bottom Line: We found potential markers of pathogenicity in all of the 11 proteins expressed by the H5 type of AIV.Our results suggest that the low pathogenicity is common to most of the subtypes of the H5 AIV while the high pathogenicity is specific to each subtype.The models were developed using public data and validated on new, unseen sequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Computational and Systems Biology, Science for Life Laboratory, Uppsala University, SE-751 24, Uppsala, Sweden. zeeshan.khaliq@icm.uu.se.

ABSTRACT

Background: Polybasic cleavage sites of the hemagglutinin (HA) proteins are considered to be the most important determinants indicating virulence of the avian influenza viruses (AIV). However, evidence is accumulating that these sites alone are not sufficient to establish high pathogenicity. There need to exist other sites located on the HA protein outside the cleavage site or on the other proteins expressed by AIV that contribute to the pathogenicity.

Results: We employed rule-based computational modeling to construct a map, with high statistical significance, of amino acid (AA) residues associated to pathogenicity in 11 proteins of the H5 type viruses. We found potential markers of pathogenicity in all of the 11 proteins expressed by the H5 type of AIV. AA mutations S-43(HA1)-D, D-83(HA1)-A in HA; S-269-D, E-41-H in NA; S-48-N, K-212-N in NS1; V-166-A in M1; G-14-E in M2; K-77-R, S-377-N in NP; and Q-48-P in PB1-F2 were identified as having a potential to shift the pathogenicity from low to high. Our results suggest that the low pathogenicity is common to most of the subtypes of the H5 AIV while the high pathogenicity is specific to each subtype. The models were developed using public data and validated on new, unseen sequences.

Conclusions: Our models explicitly define a viral genetic background required for the virus to be highly pathogenic and thus confirm the hypothesis of the presence of pathogenicity markers beyond the cleavage site.

No MeSH data available.


Related in: MedlinePlus

AA’s appearing in the most significant rules marked on the 3D structures of different proteins. AA residues appearing in the rules are shown as spheres. Positions from the high pathogenicity rules are shown in blue, positions from the low pathogenicity rules are in magenta and mutations associated with the shift of pathogenicity from low to high as defined by the rules are shown in red. a Mapping of amino acid positions associated with pathogenicity from the rules onto 3D structure of the HA protein of Influenza A virus (A/Hubei/1/2010 (H5N1)) (PDB: 4KTH). Chain A (HA1 residues) and chain B (HA2 residues) are presented in green, while the rest of the trimer is shown in gray. b A cartoon representation of chains A, B, C and D of the NA protein with AA positions from the rules (PDBID: 2HU4). Chain A, the one marked with rule positions, is shown in green and the others in gray. Residue R-371, shown as a sphere in orange, is a part of the catalytic site of the protein. Cyan spheres constitute Oseltamivir 2, a substrate bound to the protein. c A cartoon representation of the NP protein trimer (PDBID: 2IQH) with positions from the rules. Chain A is shown in green and the others are in gray. d AA’s from the rules marked on a cartoon representation of NS1 (PDBID: 3FST). e A cartoon representation of the PB2 protein cap-binding domain (PDBID: 4CB4) with AA’s from the rules
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Fig3: AA’s appearing in the most significant rules marked on the 3D structures of different proteins. AA residues appearing in the rules are shown as spheres. Positions from the high pathogenicity rules are shown in blue, positions from the low pathogenicity rules are in magenta and mutations associated with the shift of pathogenicity from low to high as defined by the rules are shown in red. a Mapping of amino acid positions associated with pathogenicity from the rules onto 3D structure of the HA protein of Influenza A virus (A/Hubei/1/2010 (H5N1)) (PDB: 4KTH). Chain A (HA1 residues) and chain B (HA2 residues) are presented in green, while the rest of the trimer is shown in gray. b A cartoon representation of chains A, B, C and D of the NA protein with AA positions from the rules (PDBID: 2HU4). Chain A, the one marked with rule positions, is shown in green and the others in gray. Residue R-371, shown as a sphere in orange, is a part of the catalytic site of the protein. Cyan spheres constitute Oseltamivir 2, a substrate bound to the protein. c A cartoon representation of the NP protein trimer (PDBID: 2IQH) with positions from the rules. Chain A is shown in green and the others are in gray. d AA’s from the rules marked on a cartoon representation of NS1 (PDBID: 3FST). e A cartoon representation of the PB2 protein cap-binding domain (PDBID: 4CB4) with AA’s from the rules

Mentions: AA residues at positions 138 and 212 appearing in the LP rules and AA residue at position 108, adjacent to position 107 from our rules, have previously been linked with pathogenicity [24]. AA residue at position 320HA1, appearing in the LP rules, is a residue flanking the cleavage site on one side and is also shown previously to affect pathogenicity [25]. AA residues at positions 42HA1 and 274HA1, which are adjacent to residues at positions 43HA1 and 275HA1 appearing in our rules, make a di-sulfide bond (UniProt: O56140). AA positions from the strongest rules for HA are shown in Fig. 3a.Fig. 3


A complete map of potential pathogenicity markers of avian influenza virus subtype H5 predicted from 11 expressed proteins.

Khaliq Z, Leijon M, Belák S, Komorowski J - BMC Microbiol. (2015)

AA’s appearing in the most significant rules marked on the 3D structures of different proteins. AA residues appearing in the rules are shown as spheres. Positions from the high pathogenicity rules are shown in blue, positions from the low pathogenicity rules are in magenta and mutations associated with the shift of pathogenicity from low to high as defined by the rules are shown in red. a Mapping of amino acid positions associated with pathogenicity from the rules onto 3D structure of the HA protein of Influenza A virus (A/Hubei/1/2010 (H5N1)) (PDB: 4KTH). Chain A (HA1 residues) and chain B (HA2 residues) are presented in green, while the rest of the trimer is shown in gray. b A cartoon representation of chains A, B, C and D of the NA protein with AA positions from the rules (PDBID: 2HU4). Chain A, the one marked with rule positions, is shown in green and the others in gray. Residue R-371, shown as a sphere in orange, is a part of the catalytic site of the protein. Cyan spheres constitute Oseltamivir 2, a substrate bound to the protein. c A cartoon representation of the NP protein trimer (PDBID: 2IQH) with positions from the rules. Chain A is shown in green and the others are in gray. d AA’s from the rules marked on a cartoon representation of NS1 (PDBID: 3FST). e A cartoon representation of the PB2 protein cap-binding domain (PDBID: 4CB4) with AA’s from the rules
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Related In: Results  -  Collection

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Fig3: AA’s appearing in the most significant rules marked on the 3D structures of different proteins. AA residues appearing in the rules are shown as spheres. Positions from the high pathogenicity rules are shown in blue, positions from the low pathogenicity rules are in magenta and mutations associated with the shift of pathogenicity from low to high as defined by the rules are shown in red. a Mapping of amino acid positions associated with pathogenicity from the rules onto 3D structure of the HA protein of Influenza A virus (A/Hubei/1/2010 (H5N1)) (PDB: 4KTH). Chain A (HA1 residues) and chain B (HA2 residues) are presented in green, while the rest of the trimer is shown in gray. b A cartoon representation of chains A, B, C and D of the NA protein with AA positions from the rules (PDBID: 2HU4). Chain A, the one marked with rule positions, is shown in green and the others in gray. Residue R-371, shown as a sphere in orange, is a part of the catalytic site of the protein. Cyan spheres constitute Oseltamivir 2, a substrate bound to the protein. c A cartoon representation of the NP protein trimer (PDBID: 2IQH) with positions from the rules. Chain A is shown in green and the others are in gray. d AA’s from the rules marked on a cartoon representation of NS1 (PDBID: 3FST). e A cartoon representation of the PB2 protein cap-binding domain (PDBID: 4CB4) with AA’s from the rules
Mentions: AA residues at positions 138 and 212 appearing in the LP rules and AA residue at position 108, adjacent to position 107 from our rules, have previously been linked with pathogenicity [24]. AA residue at position 320HA1, appearing in the LP rules, is a residue flanking the cleavage site on one side and is also shown previously to affect pathogenicity [25]. AA residues at positions 42HA1 and 274HA1, which are adjacent to residues at positions 43HA1 and 275HA1 appearing in our rules, make a di-sulfide bond (UniProt: O56140). AA positions from the strongest rules for HA are shown in Fig. 3a.Fig. 3

Bottom Line: We found potential markers of pathogenicity in all of the 11 proteins expressed by the H5 type of AIV.Our results suggest that the low pathogenicity is common to most of the subtypes of the H5 AIV while the high pathogenicity is specific to each subtype.The models were developed using public data and validated on new, unseen sequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology, Computational and Systems Biology, Science for Life Laboratory, Uppsala University, SE-751 24, Uppsala, Sweden. zeeshan.khaliq@icm.uu.se.

ABSTRACT

Background: Polybasic cleavage sites of the hemagglutinin (HA) proteins are considered to be the most important determinants indicating virulence of the avian influenza viruses (AIV). However, evidence is accumulating that these sites alone are not sufficient to establish high pathogenicity. There need to exist other sites located on the HA protein outside the cleavage site or on the other proteins expressed by AIV that contribute to the pathogenicity.

Results: We employed rule-based computational modeling to construct a map, with high statistical significance, of amino acid (AA) residues associated to pathogenicity in 11 proteins of the H5 type viruses. We found potential markers of pathogenicity in all of the 11 proteins expressed by the H5 type of AIV. AA mutations S-43(HA1)-D, D-83(HA1)-A in HA; S-269-D, E-41-H in NA; S-48-N, K-212-N in NS1; V-166-A in M1; G-14-E in M2; K-77-R, S-377-N in NP; and Q-48-P in PB1-F2 were identified as having a potential to shift the pathogenicity from low to high. Our results suggest that the low pathogenicity is common to most of the subtypes of the H5 AIV while the high pathogenicity is specific to each subtype. The models were developed using public data and validated on new, unseen sequences.

Conclusions: Our models explicitly define a viral genetic background required for the virus to be highly pathogenic and thus confirm the hypothesis of the presence of pathogenicity markers beyond the cleavage site.

No MeSH data available.


Related in: MedlinePlus