Molecular Determinants of Virulence and Stability of a Reporter-Expressing H5N1 Influenza A Virus

Journal of Virology
Dongming ZhaoYoshihiro Kawaoka

Abstract

We previously reported that an H5N1 virus carrying the Venus reporter gene, which was inserted into the NS gene segment from the A/Puerto Rico/8/1934(H1N1) virus (Venus-H5N1 virus), became more lethal to mice, and the reporter gene was stably maintained after mouse adaptation compared with the wild-type Venus-H5N1 (WT-Venus-H5N1) virus. However, the basis for this difference in virulence and Venus stability was unclear. Here, we investigated the molecular determinants behind this virulence and reporter stability by comparing WT-Venus-H5N1 virus with a mouse-adapted Venus-H5N1 (MA-Venus-H5N1) virus. To determine the genetic basis for these differences, we used reverse genetics to generate a series of reassortants of these two viruses. We found that reassortants with PB2 from MA-Venus-H5N1 (MA-PB2), MA-PA, or MA-NS expressed Venus more stably than did WT-Venus-H5N1 virus. We also found that a single mutation in PB2 (V25A) or in PA (R443K) increased the virulence of the WT-Venus-H5N1 virus in mice and that the presence of both of these mutations substantially enhanced the pathogenicity of the virus. Our results suggest roles for PB2 and PA in the stable maintenance of a foreign protein as an NS1 fusion protein in influenza A virus...Continue Reading

References

Jan 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·Y Kawaoka, R G Webster
Aug 4, 1999·Proceedings of the National Academy of Sciences of the United States of America·G NeumannY Kawaoka
Mar 23, 2004·Nucleic Acids Research·Robert C Edgar
Jun 9, 2004·Virology·Christian KittelAndrej Egorov
Dec 13, 2005·Proceedings of the National Academy of Sciences of the United States of America·G GabrielJ Stech
Dec 15, 2005·Journal of Virology·John F ReganTristram G Parslow
Mar 15, 2006·The Journal of Experimental Medicine·Rachelle SalomonErich Hoffmann
Sep 15, 2006·Journal of Virology·Zejun LiHualan Chen
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
Sep 13, 2008·Annual Review of Microbiology·Nadia NaffakhSylvie van der Werf
Mar 7, 2009·The Journal of General Virology·Nicole C RobbErvin Fodor
Nov 4, 2009·Cell Research·Gabriele NeumannYoshihiro Kawaoka
Jun 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Balaji ManicassamyAdolfo García-Sastre
Oct 7, 2010·Proceedings of the National Academy of Sciences of the United States of America·Daniel KreiselMark J Miller
Dec 15, 2010·Nature Methods·Mark R LooneyMatthew F Krummel
Mar 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yipeng SunJinhua Liu
Oct 9, 2012·The Journal of Clinical Investigation·Julie HelftMiriam Merad
Jan 22, 2013·Cell Reports·Mark A ChuaBenjamin R Tenoever
Apr 26, 2013·The New England Journal of Medicine·Qun LiZijian Feng
Sep 12, 2013·Nature Communications·Weiqi PanLing Chen
Dec 29, 2013·Journal of Virology·Seiya YamayoshiYoshihiro Kawaoka
Mar 26, 2015·Nature Communications·Satoshi FukuyamaYoshihiro Kawaoka

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Citations

Jun 27, 2018·Proceedings of the National Academy of Sciences of the United States of America·Hiroshi UekiYoshihiro Kawaoka

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