PLoS Pathogens: Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus

Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus

Influenza viruses that originate from avian species likely have to acquire adapting amino acid changes to replicate efficiently in mammals. Two amino acid changes in the polymerase PB2 protein—a glutamic acid to lysine change at position 627 or an aspartic acid to asparagine change at position 701—are known to allow influenza viruses of avian origin to replicate efficiently in mammals. Interestingly, the pandemic H1N1 viruses (which possess an avian-like PB2 gene) do not encode the ‘human-type’ amino acids PB2-627K and PB2-701N. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of PB2-627K and allows efficient replication of highly pathogenic H5N1 and pandemic H1N1 viruses in mammalian species. We also present the X-ray crystal structure of the C-terminal portion of a pandemic H1N1 PB2 protein. The basic amino acid at position 591 fills a distinctive cleft found in the PB2 proteins of H5N1 viruses. We also speculate on the biological significance of the altered surface of the H1N1 PB2 protein.

References
Shinya Yamada1, Masato Hatta2, Bart L. Staker3,4, Shinji Watanabe2, Masaki Imai2, Kyoko Shinya5, Yuko Sakai-Tagawa1, Mutsumi Ito1, Makoto Ozawa2,6, Tokiko Watanabe2, Saori Sakabe1,7, Chengjun Li2, Jin Hyun Kim2, Peter J. Myler4,8,9, Isabelle Phan4,8, Amy Raymond3,4, Eric Smith3,4, Robin Stacy4,8, Chairul A. Nidom10,11, Simon M. Lank12, Roger W. Wiseman12, Benjamin N. Bimber12, David H. O'Connor12,13, Gabriele Neumann2, Lance J. Stewart3,4*, Yoshihiro Kawaoka1,2,5,6,7,14*

1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan, 2 Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 3 Emerald BioStructures, Inc., Bainbridge Island, Washington, United States of America, 4 Seattle Structural Genomics Center for Infectious Disease, Washington, United States of America, 5 Department of Microbiology and Infectious Diseases, Kobe University, Hyogo, Japan, 6 Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan, 7 ERATO Infection-Induced Host Responses Project, Saitama, Japan, 8 Seattle Biomedical Research Institute, Seattle, Washington, United States of America, 9 Departments of Global Health and Medical Education & Biomedical Informatics, University of Washington, Seattle, Washington, United States of America, 10 Faculty of Veterinary Medicine, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia, 11 Collaborating Research Center-Emerging and Reemerging Infectious Diseases, Tropical Disease Centre, Airlangga University, Surabaya, Indonesia, 12 Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 13 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 14 Creative Research Initiative, Sousei, Hokkaido University, Sapporo, Japan

Abstract
Two amino acids (lysine at position 627 or asparagine at position 701) in the polymerase subunit PB2 protein are considered critical for the adaptation of avian influenza A viruses to mammals. However, the recently emerged pandemic H1N1 viruses lack these amino acids. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of lysine at position 627 and confers efficient viral replication to pandemic H1N1 viruses in mammals. Moreover, a basic amino acid at position 591 of PB2 substantially increased the lethality of an avian H5N1 virus in mice. We also present the X-ray crystallographic structure of the C-terminus of a pandemic H1N1 virus PB2 protein. Arginine at position 591 fills the cleft found in H5N1 PB2 proteins in this area, resulting in differences in surface shape and charge for H1N1 PB2 proteins. These differences may affect the protein's interaction with viral and/or cellular factors, and hence its ability to support virus replication in mammals.

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PLoS Pathogens: Biological and Structural Characterization of a Host-Adapting Amino Acid in Influenza Virus



GRIPE A
Actualidad Ultimas noticias - JANOes
Encuentran la clave de la rápida expansión del virus de la gripe A
JANO.es · 06 Agosto 2010 09:43

Una investigación identifica en el virus la presencia de un aminoácido imprescindible para que la cepa se transmita de animales a humanos y se replique de forma eficiente.



Virus de la gripe A
Un equipo de investigadores de la Universidad de Wisconsin y del Centro de Genómica Estructural de Enfermedades Infecciosas de Seattle (SSCGID), Estados Unidos, ha descubierto por qué el virus de la gripe A/H1N1 tiene un alto índice de expansión entre los seres humanos.
La investigación, publicada en la revista PLoS Pathogens, ha identificado en el nuevo virus la presencia anómala de un aminoácido -la lisina- que, junto a la asparagina, es imprescindible para que la cepa salte de los animales a los humanos y se replique de forma eficiente entre las personas.

En concreto, los científicos atribuyen la fuerte expansión de la cepa H1N1 a la localización "totalmente diferente" de la lisina en la cadena de proteínas del virus, mutación que le otorgaría la habilidad para adaptarse y colonizar las células humanas con especial eficacia. "Este descubrimiento podría ayudar a predecir cómo de virulenta va a ser una cepa de la gripe y prever futuras pandemias", asegura el director del estudio, Yoshihiro Kawaoka.

Interacción del virus con las células del anfitrión
El informe también incluye nuevos datos sobre la estructura tridimensional de la proteína PB2 -procedente de las aves- dentro del virus, obtenidos gracias a una nueva tecnología de rayos X cristalográficos desarrollada por el centro de Seattle.

"Esta nueva información -comenta Kawaoka- proporciona una perspectiva esencial sobre cómo interactúa el virus con las células del anfitrión, algo que podría ayudar en el desarrollo de nuevos antivirales que puedan impedir la dispersión de cepas de la gripe que usen el mismo truco de la lisina para infectar células humanas".

Asimismo, según explica el responsable del SSCGID, Bart L. Staker, estos datos estructurales también revelan mutaciones en la capa superficial de la proteína aviar del H1N1 que, a su vez, podrían ser las responsables de frustrar las defensas de la célula humana, impidiendo que ésta inhiba la infección.

PLoS Pathog 6(8): e1001034. doi:10.1371/journal.ppat.1001034
http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1001034

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http://www.ssgcid.org/home/index.asp


Universidad de Wisconsin
http://www.wisc.edu/
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