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Adaptive mutations resulting in enhanced polymerase activity contribute to high virulence of influenza A virus in mice.
J Virol. 2009 Jul; 83(13):6673-80.JV

Abstract

High virulence of influenza virus A/Puerto Rico/8/34 in mice carrying the Mx1 resistance gene was recently shown to be determined by the viral surface proteins and the viral polymerase. Here, we demonstrated high-level polymerase activity in mammalian host cells but not avian host cells and investigated which mutations in the polymerase subunits PB1, PB2, and PA are critical for increased polymerase activity and high virus virulence. Mutational analyses demonstrated that an isoleucine-to-valine change at position 504 in PB2 was the most critical and strongly enhanced the activity of the reconstituted polymerase complex. An isoleucine-to-leucine change at position 550 in PA further contributed to increased polymerase activity and high virulence, whereas all other mutations in PB1, PB2, and PA were irrelevant. To determine whether this pattern of acquired mutations represents a preferred viral strategy to gain virulence, two independent new virus adaptation experiments were performed. Surprisingly, the conservative I504V change in PB2 evolved again and was the only mutation present in an aggressive virus variant selected during the first adaptation experiment. In contrast, the virulent virus selected in the second adaptation experiment had a lysine-to-arginine change at position 208 in PB1 and a glutamate-to-glycine change at position 349 in PA. These results demonstrate that a variety of minor amino acid changes in the viral polymerase can contribute to enhanced virulence of influenza A virus. Interestingly, all virulence-enhancing mutations that we identified in this study resulted in substantially increased viral polymerase activity.

Authors+Show Affiliations

Department of Virology, University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19403683

Citation

Rolling, Thierry, et al. "Adaptive Mutations Resulting in Enhanced Polymerase Activity Contribute to High Virulence of Influenza a Virus in Mice." Journal of Virology, vol. 83, no. 13, 2009, pp. 6673-80.
Rolling T, Koerner I, Zimmermann P, et al. Adaptive mutations resulting in enhanced polymerase activity contribute to high virulence of influenza A virus in mice. J Virol. 2009;83(13):6673-80.
Rolling, T., Koerner, I., Zimmermann, P., Holz, K., Haller, O., Staeheli, P., & Kochs, G. (2009). Adaptive mutations resulting in enhanced polymerase activity contribute to high virulence of influenza A virus in mice. Journal of Virology, 83(13), 6673-80. https://doi.org/10.1128/JVI.00212-09
Rolling T, et al. Adaptive Mutations Resulting in Enhanced Polymerase Activity Contribute to High Virulence of Influenza a Virus in Mice. J Virol. 2009;83(13):6673-80. PubMed PMID: 19403683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adaptive mutations resulting in enhanced polymerase activity contribute to high virulence of influenza A virus in mice. AU - Rolling,Thierry, AU - Koerner,Iris, AU - Zimmermann,Petra, AU - Holz,Kristian, AU - Haller,Otto, AU - Staeheli,Peter, AU - Kochs,Georg, Y1 - 2009/04/29/ PY - 2009/5/1/entrez PY - 2009/5/1/pubmed PY - 2009/6/19/medline SP - 6673 EP - 80 JF - Journal of virology JO - J Virol VL - 83 IS - 13 N2 - High virulence of influenza virus A/Puerto Rico/8/34 in mice carrying the Mx1 resistance gene was recently shown to be determined by the viral surface proteins and the viral polymerase. Here, we demonstrated high-level polymerase activity in mammalian host cells but not avian host cells and investigated which mutations in the polymerase subunits PB1, PB2, and PA are critical for increased polymerase activity and high virus virulence. Mutational analyses demonstrated that an isoleucine-to-valine change at position 504 in PB2 was the most critical and strongly enhanced the activity of the reconstituted polymerase complex. An isoleucine-to-leucine change at position 550 in PA further contributed to increased polymerase activity and high virulence, whereas all other mutations in PB1, PB2, and PA were irrelevant. To determine whether this pattern of acquired mutations represents a preferred viral strategy to gain virulence, two independent new virus adaptation experiments were performed. Surprisingly, the conservative I504V change in PB2 evolved again and was the only mutation present in an aggressive virus variant selected during the first adaptation experiment. In contrast, the virulent virus selected in the second adaptation experiment had a lysine-to-arginine change at position 208 in PB1 and a glutamate-to-glycine change at position 349 in PA. These results demonstrate that a variety of minor amino acid changes in the viral polymerase can contribute to enhanced virulence of influenza A virus. Interestingly, all virulence-enhancing mutations that we identified in this study resulted in substantially increased viral polymerase activity. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/19403683/Adaptive_mutations_resulting_in_enhanced_polymerase_activity_contribute_to_high_virulence_of_influenza_A_virus_in_mice_ L2 - https://journals.asm.org/doi/10.1128/JVI.00212-09?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -