title: Molecular basis of efficient replication and pathogenicity of H9N2 avian influenza viruses in mice.
abstract: H9N2 subtype avian influenza viruses (AIVs) have shown expanded host range and can infect mammals, such as humans and swine. To date the mechanisms of mammalian adaptation and interspecies transmission of H9N2 AIVs remain poorly understood. To explore the molecular basis determining mammalian adaptation of H9N2 AIVs, we compared two avian field H9N2 isolates in a mouse model: one (A/chicken/Guangdong/TS/2004, TS) is nonpathogenic, another one (A/chicken/Guangdong/V/2008, V) is lethal with efficient replication in mouse brains. In order to determine the basis of the differences in pathogenicity and brain tropism between these two viruses, recombinants with a single gene from the TS (or V) virus in the background of the V (or TS) virus were generated using reverse genetics and evaluated in a mouse model. The results showed that the PB2 gene is the major factor determining the virulence in the mouse model although other genes also have variable impacts on virus replication and pathogenicity. Further studies using PB2 chimeric viruses and mutated viruses with a single amino acid substitution at position 627 [glutamic acid (E) to lysine, (K)] in PB2 revealed that PB2 627K is critical for pathogenicity and viral replication of H9N2 viruses in mouse brains. All together, these results indicate that the PB2 gene and especially position 627 determine virus replication and pathogenicity in mice. This study provides insights into the molecular basis of mammalian adaptation and interspecies transmission of H9N2 AIVs.
authors: College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
authors: Xiaokang
authors: X
authors: Li
authors: Wenbao
authors: W
authors: Qi
authors: Jun
authors: J
authors: He
authors: Zhangyong
authors: Z
authors: Ning
authors: Yue
authors: Y
authors: Hu
authors: Jin
authors: J
authors: Tian
authors: Peirong
authors: P
authors: Jiao
authors: Chenggang
authors: C
authors: Xu
authors: Jianxin
authors: J
authors: Chen
authors: Juergen
authors: J
authors: Richt
authors: Wenjun
authors: W
authors: Ma
authors: Ming
authors: M
authors: Liao
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000473:pathology / Q000821:virology; D002645:Chickens; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D053127:Influenza A Virus, H9N2 Subtype / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D005585:Influenza in Birds / Q000821:virology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000821:virology*; D011995:Recombination, Genetic / Q000235:genetics; D020539:Sequence Analysis, Protein; D016019:Survival Analysis; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics; D014774:Virulence; D014779:Virus Replication / Q000235:genetics*
chemical_list: D000596:Amino Acids; D050505:Mutant Proteins; D014764:Viral Proteins