Our long-term goal is to understand the emergence of pandemic influenza viruses, such as the 1918 influenza virus that caused the most devastating outbreak of an infectious disease on record. In particular, we are asking two questions: (i) how likely is the emergence of a pandemic strain comparable to the 1918 virus?;and (ii) what are the molecular features that accounted for the unprecedented virulence of the 1918 virus? Our studies have revealed that avian influenza virus genes that encode 1918 virus-like proteins still exist in nature, suggesting that 1918-like pandemic viruses may emerge in the future.
In Aim 1, we will therefore assess the risk for the emergence of 1918 virus-like pandemic influenza viruses. To assess this risk, we have generated a 1918-like avian influenza virus comprising avian influenza viral segments that encode 1918-like proteins. We will introduce 1918 viral amino acids into this virus to identify changes that are critical for pathogenicity. In a parallel approach, we have generated mutant 1918 viruses in which one gene at a time is replaced with its closest avian relative (as determined by protein homology). The introduction of 1918 amino acids into the 'avian'gene/protein will reveal amino acids that are critical for 1918 virus pathogenicity. We and others have identified the HA gene as an important determinant of the unprecedented virulence of the 1918 influenza virus. The HA protein carries out two critical functions in the viral life cycle - receptor-binding and fusion of the viral and endosomal membranes. Currently, it is not known if the 1918 HA protein differs in its receptor-binding properties and/or fusion kinetics from contemporary human viruses, and if potential differences contributed to the high virulence of the 1918 virus.
In Aim 2, we will therefore test whether the 1918 HA protein differs from that of contemporary human viruses in its receptor-binding properties. These features may be affected by the HA glycosylation pattern, prompting us to test the significance of the atypical 1918 HA glycosylation pattern for virulence. In addition, we will characterize the fusion kinetics of the 1918 HA protein, with particular emphasis on the characterization of a previously unrecognized histidine patch in the 1918 HA protein that is thought to affect fusion. In addition to the HA gene, the viral replication complex has been identified as a determinant of host range and pathogenicity. Our preliminary data also suggest a role for the 1918 virus replication complex in the virulence of the 1918 virus. However, the exact contributions of the components of the replication complex to increased virulence and the underlying mechanisms (including effects on host cell responses) are currently unknown, a gap in knowledge that we propose to fill in Aim 3. Collectively, these studies are designed to address two critical questions in influenza virus research - why was the 1918 virus highly pathogenic, and what is the risk for emergence of another 1918-like virus?
Our long-term goal is to understand the likelihood of the emergence of 1918-like pandemic influenza viruses, and the mechanisms that accounted for the unprecedented virulence of the 1918 pandemic influenza virus. Such knowledge will help us to prepare for future influenza pandemics and to quickly recognize influenza virus strains with pandemic potential.
|Forero, Adriana; Tisoncik-Go, Jennifer; Watanabe, Tokiko et al. (2016) The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice. J Virol 90:2240-53|
|Moncla, Louise H; Zhong, Gongxun; Nelson, Chase W et al. (2016) Selective Bottlenecks Shape Evolutionary Pathways Taken during Mammalian Adaptation of a 1918-like Avian Influenza Virus. Cell Host Microbe 19:169-80|
|Watanabe, Tokiko; Kawaoka, Yoshihiro (2015) Influenza virus-host interactomes as a basis for antiviral drug development. Curr Opin Virol 14:71-8|
|Watanabe, Tokiko; Kawakami, Eiryo; Shoemaker, Jason E et al. (2014) Influenza virus-host interactome screen as a platform for antiviral drug development. Cell Host Microbe 16:795-805|
|Watanabe, Tokiko; Zhong, Gongxun; Russell, Colin A et al. (2014) Circulating avian influenza viruses closely related to the 1918 virus have pandemic potential. Cell Host Microbe 15:692-705|
|Watanabe, Tokiko; Watanabe, Shinji; Maher, Eileen A et al. (2014) Pandemic potential of avian influenza A (H7N9) viruses. Trends Microbiol 22:623-31|
|Watanabe, Tokiko; Tisoncik-Go, Jennifer; Tchitchek, Nicolas et al. (2013) 1918 Influenza virus hemagglutinin (HA) and the viral RNA polymerase complex enhance viral pathogenicity, but only HA induces aberrant host responses in mice. J Virol 87:5239-54|
|Neumann, Gabriele; Kawaoka, Yoshihiro (2011) The first influenza pandemic of the new millennium. Influenza Other Respir Viruses 5:157-66|
|Ozawa, Makoto; Kawaoka, Yoshihiro (2011) Taming influenza viruses. Virus Res 162:8-11|
|Fukuyama, Satoshi; Kawaoka, Yoshihiro (2011) The pathogenesis of influenza virus infections: the contributions of virus and host factors. Curr Opin Immunol 23:481-6|
Showing the most recent 10 out of 14 publications