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J Virol. 2010 Jun 30. [Epub ahead of print]
Adaptation of pandemic H1N1 influenza viruses in mice.
Ilyushina NA, Khalenkov AM, Seiler JP, Forrest HL, Bovin NV, Marjuki H, Barman S, Webster RG, Webby RJ.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA; The D.I. Ivanovsky Institute of Virology RAMS, Moscow 123098, Russia; Shemyakin Institute of Bioorganic Chemistry, Moscow 117997, Russia; Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
Abstract
The molecular mechanism by which pandemic 2009 influenza A viruses were able to sufficiently adapt to humans is largely unknown. Subsequent human infections with novel H1N1 influenza prompted an investigation of the molecular determinants of their host range and pathogenicity in mammals. To address this problem, we assessed the genetic basis for increased virulence of A/CA/04/09 (H1N1) and A/TN/1-560/09 (H1N1) isolates, which are not lethal for mice, in a new mammalian host by promoting their mouse adaptation. The resulting mouse lung-adapted variants showed significantly enhanced growth characteristics in eggs, extended extra-pulmonary tissue tropism, and pathogenicity in mice. All mouse-adapted viruses except A/TN/1-560/09-MA2 grew faster and to higher titers in cells than the original strains. We found that 10 amino acid changes in the ribonucleoprotein (RNP) complex (PB2-E158G/A, PA-L295P, NP-D101G, and NP-H289Y) and hemagglutinin (HA) glycoprotein (K119N, G155E, S183P, R221K, and D222G) controlled enhanced mouse virulence of pandemic isolates. HA mutations acquired during adaptation affected viral receptor specificity by enhancing binding to alpha2,3 together with decreasing binding to alpha2,6 sialyl receptors. PB2-E158G/A and PA-L295P amino acid substitutions were responsible for the significant enhancement of transcription and replication activity of the mouse-adapted H1N1 variants. Taken together, our findings suggest that changes optimizing receptor specificity and interaction of viral polymerase components with host cellular factors are the major mechanisms that contribute to optimal competitive advantage of pandemic influenza viruses in mice. These modulators of virulence therefore may be the driving components of early evolution, which paved the way for novel 2009 viruses in mammals.
PMID: 20592084 [PubMed - as supplied by publisher]
Adaptation of pandemic H1N1 influenza viruses in mice.
Ilyushina NA, Khalenkov AM, Seiler JP, Forrest HL, Bovin NV, Marjuki H, Barman S, Webster RG, Webby RJ.
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA; The D.I. Ivanovsky Institute of Virology RAMS, Moscow 123098, Russia; Shemyakin Institute of Bioorganic Chemistry, Moscow 117997, Russia; Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38105, USA.
Abstract
The molecular mechanism by which pandemic 2009 influenza A viruses were able to sufficiently adapt to humans is largely unknown. Subsequent human infections with novel H1N1 influenza prompted an investigation of the molecular determinants of their host range and pathogenicity in mammals. To address this problem, we assessed the genetic basis for increased virulence of A/CA/04/09 (H1N1) and A/TN/1-560/09 (H1N1) isolates, which are not lethal for mice, in a new mammalian host by promoting their mouse adaptation. The resulting mouse lung-adapted variants showed significantly enhanced growth characteristics in eggs, extended extra-pulmonary tissue tropism, and pathogenicity in mice. All mouse-adapted viruses except A/TN/1-560/09-MA2 grew faster and to higher titers in cells than the original strains. We found that 10 amino acid changes in the ribonucleoprotein (RNP) complex (PB2-E158G/A, PA-L295P, NP-D101G, and NP-H289Y) and hemagglutinin (HA) glycoprotein (K119N, G155E, S183P, R221K, and D222G) controlled enhanced mouse virulence of pandemic isolates. HA mutations acquired during adaptation affected viral receptor specificity by enhancing binding to alpha2,3 together with decreasing binding to alpha2,6 sialyl receptors. PB2-E158G/A and PA-L295P amino acid substitutions were responsible for the significant enhancement of transcription and replication activity of the mouse-adapted H1N1 variants. Taken together, our findings suggest that changes optimizing receptor specificity and interaction of viral polymerase components with host cellular factors are the major mechanisms that contribute to optimal competitive advantage of pandemic influenza viruses in mice. These modulators of virulence therefore may be the driving components of early evolution, which paved the way for novel 2009 viruses in mammals.
PMID: 20592084 [PubMed - as supplied by publisher]
