Abstract
BackgroundPolybasic 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.ResultsWe 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-43HA1-D, D-83HA1-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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-015-0465-x) contains supplementary material, which is available to authorized users.
Highlights
Polybasic cleavage sites of the hemagglutinin (HA) proteins are considered to be the most important determinants indicating virulence of the avian influenza viruses (AIV)
We found potential markers of pathogenicity in all of the 11 proteins expressed by the H5 type of AIV
amino acid (AA) mutations S-43HA1-D, D-83HA1-A in HA; S-269-D, E-41-H in NA; S-48-N, K-212-N in Non structural protein 1 (NS1); V-166-A in Matrix protein 1 (M1); G-14-E in Matrix protein 2 (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
Summary
Polybasic cleavage sites of the hemagglutinin (HA) proteins are considered to be the most important determinants indicating virulence of the avian influenza viruses (AIV). Pathogenic avian influenza viruses (HPAIV) pose a threat for yet another epidemic or pandemic, which can potentially result in severe consequences for both animal and human life. High pathogenicity has been previously linked to insertions in the cleavage site of HA [6,7,8]. These insertions allow the HA0 to be cleaved by ubiquitously expressed intracellular proteases such as furin [9,10,11]
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