title: Synergism of co-mutation of two amino acid residues in NS1 protein increases the pathogenicity of influenza virus in mice.
abstract: The NS1 influenza virus gene is thought to play an important role in replication and pathogenicity during infection. Previous studies have shown that mutations in the highly pathogenic avian NS1 influenza virus gene can influence virulence. However, little is known regarding the pathogenic mechanism of the NS1 gene in low pathogenic avian influenza virus. We found that NS1 genes originating from two H3 avian influenza viruses, A/duck/Beijing/40/04 (Dk/BJ/40/04) and A/duck/Beijing/61/05 (Dk/BJ/61/05), possessing three amino acid residue differences at positions 127, 205 and 209 contributed to an altered virulence in rescued NS1 recombinant viruses on a A/WSN/33 (WSN) virus background (WSN:40NS1 and WSN:61NS1) in mice. To further determine the effect on pathogenicity, we generated a series of recombinant viruses with mutations at positions 127, 205 and 209 in the NS1 gene of WSN:61NS1. Experiments in mice indicated that when compared with WSN:61NS1, viruses with only single mutations enhanced incidence of infection in mice but were not lethal. Viruses bearing substitution of two amino acid residues in the NS1 protein replicated well in lung tissue and caused 20-100% mortality in mice. Our findings demonstrate that co-mutation of amino acid residues at multiple positions in the NS1 protein can increase the pathogenicity of influenza virus in mice.
authors.affiliation: Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, PR China.
authors.forename: Juan
authors.initials: J
authors.lastname: Pu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Guanghua
authors.initials: G
authors.lastname: Fu
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Bi
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Sun
authors.forename: Jinhua
authors.initials: J
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002642:Chick Embryo; D004195:Disease Models, Animal; D004372:Ducks; D005260:Female; D009980:Influenza A virus / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000821:virology; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D011995:Recombination, Genetic; D016019:Survival Analysis; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D037521:Virulence Factors / Q000235:genetics*
chemical_list: C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors