title: Attenuation of an influenza A virus due to alteration of its hemagglutinin-neuraminidase functional balance in mice.
abstract: Influenza A viruses possess two surface glycoproteins, hemagglutinin (HA), which binds to sialic-acid-containing receptors, and neuraminidase (NA), which removes sialic acid from host cells. It is well established that the HA-NA functional balance regulates the efficiency of virus replication. Here, we selected a plaque variant of the WSN (H1N1) strain that grew better than the wild-type virus in NA-expressing MDCK cell culture. A reverse genetics study revealed that the single mutation HA E190K, which occurs infrequently in naturally isolated H1N1 viruses, was responsible for the phenotype of this variant. Receptor assays indicated that this mutation did not affect the receptor specificity of HA but enhanced its receptor-binding affinity, resulting in altered HA-NA functional balance relative to that of the wild-type virus. We also found that this variant replicated in nasal turbinates at an equivalent level but in lungs at a lower level compared with wild-type virus, demonstrating its attenuation in mice. Together, our data demonstrated the importance of the HA-NA functional balance for influenza virus replication in an in vivo biological setting.
authors.affiliation: Department of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Gen
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamada
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kato
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Akashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Taisuke
authors.initials: T
authors.lastname: Horimoto
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism*; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity*; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000821:virology; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D014779:Virus Replication
chemical_list: C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D014764:Viral Proteins; C487630:NA protein, influenza A virus; D009439:Neuraminidase