title: A complete map of potential pathogenicity markers of avian influenza virus subtype H5 predicted from 11 expressed proteins.
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.
authors.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.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Khaliq
authors.affiliation: Department of Virology, Parasitology and Immunobiology (VIP), National Veterinary Institute (SVA), Uppsala, Sweden. mikael.leijon@sva.se.|OIE Collaborating Centre for the Biotechnology-based Diagnosis of Infectious Diseases in Veterinary Medicine, Ulls väg 2B and 26, SE-756 89, Uppsala, Sweden. mikael.leijon@sva.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Leijon
authors.affiliation: OIE Collaborating Centre for the Biotechnology-based Diagnosis of Infectious Diseases in Veterinary Medicine, Ulls väg 2B and 26, SE-756 89, Uppsala, Sweden. sandor.belak@slu.se.|Department of Biomedical Sciences and Veterinary Public Health (BVF), Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden. sandor.belak@slu.se.
authors.forename: Sándor
authors.initials: S
authors.lastname: Belák
authors.affiliation: Department of Cell and Molecular Biology, Computational and Systems Biology, Science for Life Laboratory, Uppsala University, SE-751 24, Uppsala, Sweden. jan.komorowski@icm.uu.se.|Institute of Computer Science, Polish Academy of Sciences, 01-248, Warszawa, Poland. jan.komorowski@icm.uu.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Komorowski
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001717:Birds; D019295:Computational Biology; D003198:Computer Simulation; D005819:Genetic Markers; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics*; D006801:Humans; D009980:Influenza A virus / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000821:virology*; D008954:Models, Biological; D020125:Mutation, Missense; D014764:Viral Proteins / Q000235:genetics*; D037521:Virulence Factors / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D014764:Viral Proteins; D037521:Virulence Factors; C109963:hemagglutinin, avian influenza A virus