Mutations in Hemagglutinin and Polymerase Alter the Virulence of Pandemic A(H1N1) Influenza Virus

To study the pathogenicity factors of the pandemic A(H1N1) influenza virus, a number of mutant variants of the A/Hamburg/5/2009 (H1N1)pdm09 strain were obtained through passage in chicken embryos, mouse lungs, and MDCK cell culture. After 17 lung-to-lung passages of the A/Hamburg/5/2009 in mice, the...

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Bibliographic Details
Published in:Molecular biology (New York) 2018-07, Vol.52 (4), p.556-569
Main Authors: Gambaryan, A. S., Lomakina, N. F., Boravleva, E. Y., Mochalova, L. V., Sadykova, G. K., Prilipov, A. G., Matrosovich, T. Y., Matrosovich, M. N.
Format: Article
Language:English
Subjects:
Amino acid substitution
Biochemistry
Biomedical and Life Sciences
Cell culture
Cloning
Comparative analysis
Embryos
Exo-a-sialidase
Hemagglutinins
Human Genetics
Influenza
Lethal dose
Life Sciences
Lungs
Mice
Molecular Cell Biology
Mutation
Pandemics
Pathogenicity
Pathogens
Poultry
Proteins
Virulence
Viruses
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Summary:To study the pathogenicity factors of the pandemic A(H1N1) influenza virus, a number of mutant variants of the A/Hamburg/5/2009 (H1N1)pdm09 strain were obtained through passage in chicken embryos, mouse lungs, and MDCK cell culture. After 17 lung-to-lung passages of the A/Hamburg/5/2009 in mice, the minimum lethal dose of the derived variant decreased by five orders of magnitude compared to that of the parental virus. This variant differed from the original virus by nine amino acid residues in the following viral proteins: hemagglutinin (HA), neuraminidase (NA), and components of the polymerase complex. Additional passaging of the intermediate variants and cloning made it possible to obtain pairs of strains that differed by a single amino acid substitution. Comparative analysis of replicative activity, receptor specificity, and virulence of these variants revealed two mechanisms responsible for increased pathogenicity of the virus for mice. Thus, (1) substitutions in HA (Asp225Gly or Gln226Arg) and compensatory mutation decreasing the charge of HA (Lys123Asn, Lys157Asn, Gly158Glu, Asn159Asp, or Lys212Met) altered viral receptor-binding specificity and restored the functional balance between HA and NA; (2) Phe35Leu substitution in the PA protein increased viral polymerase activity.
ISSN:0026-8933
1608-3245
DOI:10.1134/S0026893318040052