[Source: Journal of Virology, full text: (LINK). Abstract, edited.]
1918 HA and the viral RNA polymerase complex enhance viral pathogenicity, but only HA induces aberrant host responses in mice
Tokiko Watanabe 1,2,†, Jennifer Tisoncik-Go 3, Nicolas Tchitchek 3, Shinji Watanabe 1,2, Arndt G. Benecke 3,4, Michael G. Katze 3 and Yoshihiro Kawaoka 1,2,5,6,†
Author Affiliations: 1Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA 2ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan 3Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 98195 4Université Pierre et Marie Curie, Centre National de la Recherche Scientifique UMR7224, Paris, France 5Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan 6Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
The 1918 pandemic influenza virus was the most devastating infectious agent in human history, causing fatal pneumonia and an estimated 20-50 million deaths worldwide. Previous studies indicate a prominent role of the HA gene in efficient replication and high virulence of the 1918 virus in mice. It is, however, still unclear whether the high replication ability or the 1918 HA gene is required for 1918 virus to exhibit high virulence in mice. Here, we examined the biological properties of reassortant viruses between the 1918 virus and a contemporary human H1N1 virus (A/Kawasaki/173/2001; K173) in a mouse model. In addition to the 1918 HA, we demonstrated the role of viral RNA replication complex in efficient replication of viruses in mouse lungs, whereas only HA gene is responsible for lethality in mice. Global gene expression profiling of infected mouse lungs revealed 1918 HA was sufficient to induce transcriptional changes similar to the 1918 virus, despite difference in lymphocyte gene expression. Increased expression of genes associated with the acute phase response and protein ubiquitination pathway were enriched during 1918 and 1918HA/K173 infections, whereas reassortant viruses bearing the 1918 viral RNA polymerase complex induced transcriptional changes similar to K173 virus. Taken together, these data suggest HA and the viral RNA polymerase complex are critical determinants of Spanish influenza pathogenesis, but only HA, and not the viral RNA polymerase complex and NP, is responsible for extreme host responses observed in mice infected with the 1918 influenza virus.
† Correspondence should be addressed to Tokiko Watanabe or Yoshihiro Kawaoka, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 575 Science Drive, Madison, WI 53711, USA; Phone: (608) 265-4925, Fax: (608) 265-5622, E-Mail: firstname.lastname@example.org or email@example.com
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