The Role of the Nuclear Import Machinery in the Adaptation of Avian Influenza A Viruses to the Mammalian Host

• Applicant: Professorin Dr. Gülsah Gabriel
• Subject Area: Virology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 123002173

• Final Report Year: 2017

Final Report Abstract

Within the funding period of the Emmy Noether Program, we were able to report several achievements. First, we could show that the cellular import machinery mainly consisting of the importin-α/ß pathway plays a key role in influenza A virus avian-mammalian adaptation. Due to the sequence divergence between chicken and humans, avian influenza viruses need to adapt to the mammalian import machinery by acquiring adaptive mutations in their polymerase complex (PB2 627K/PB2 701N). The optimal polymerase-importin interplay then enables efficient nuclear access to the viral polymerase complex that in turn leads to increased replicative fitness in human cells. Second, we could show that these polymeraseimportin interactions are not only crucial for virus replication in vitro but also play a key role in influenza virus pathogenesis in mammals. Third, we could show that the nuclear import machinery also contributes to enhanced replication of other viruses, such as Ebola and MERS-CoV viruses. These findings suggest that common molecular pathways exist, albeit the detailed mechanisms by which the respective viruses utilize the nuclear import machinery seem to be different and need further elucidation. In summary, our findings improve our current understanding of the molecular basis of influenza virus interspecies transmission and provide a basis for the development of novel and potentially broad-spectrum antiviral therapies in future.

Publications

• (2014) Importin-α7 is required for enhanced influenza A virus replication in the alveolar epithelium and severe lung damage in mice. Journal of virology 88 (14) 8166–8179
  Resa-Infante, Patricia; Thieme, René; Ernst, Thomas; Arck, Petra C.; Ittrich, Harald; Reimer, Rudolph; Gabriel, Gülsah
  
• (2015) Adaptive Mutations That Occurred during Circulation in Humans of H1N1 Influenza Virus in the 2009 Pandemic Enhance Virulence in Mice. Journal of virology (14) 7329–7337
  Otte, A.; Sauter, M.; Daxer, M. A.; McHardy, A. C.; Klingel, K.; Gabriel, G.
  
• (2015) Importin-α7 Is Involved in the Formation of Ebola Virus Inclusion Bodies but Is Not Essential for Pathogenicity in Mice. The Journal of infectious diseases 212 Suppl 2 S316-21
  Gabriel, Gülsah; Feldmann, Friederike; Reimer, Rudolph; Thiele, Swantje; Fischer, Meike; Hartmann, Enno; Bader, Michael; Ebihara, Hideki; Hoenen, Thomas; Feldmann, Heinz
  
• (2015) Targeting Importin-α7 as a Therapeutic Approach against Pandemic Influenza Viruses. Journal of virology 89( 17) 9010–9020
  Resa-Infante, Patricia; Paterson, Duncan; Bonet, Jaume; Otte, Anna; Oliva, Baldo; Fodor, Ervin; Gabriel, Gülsah
  
• (2011) Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus. Nature communications 2 156
  Gabriel, Gülsah; Klingel, Karin; Otte, Anna; Thiele, Swantje; Hudjetz, Ben; Arman-Kalcek, Gökhan; Sauter, Martina; Shmidt, Tatiana; Rother, Franziska; Baumgarte, Sigrid; Keiner, Björn; Hartmann, Enno; Bader, Michael; Brownlee, George G.; Fodor, Ervin; Kle
  
• (2012). Human‐like PB2 627K Influenza Virus Polymerase Activity Is Regulated by Importin‐a1 and ‐a7. PLoS Pathogens, 8(1):e1002488
  Hudjetz B and Gabriel G
  
• (2016) Evolution of 2009 H1N1 influenza viruses during the pandemic correlates with increased viral pathogenicity and transmissibility in the ferret model. In: Sci Rep 6 (1) 28583
  Otte, Anna; Marriott, Anthony C.; Dreier, Carola; Dove, Brian; Mooren, Kyra; Klingen, Thorsten R.; Sauter, Martina; Thompson, Katy-Anne; Bennett, Allan; Klingel, Karin; van Riel, Debby; McHardy, Alice C.; Carroll, Miles W.; Gabriel, Gülsah
  
• (2016) Highly Pathogenic Avian Influenza A(H5N1) Virus among Poultry, Ghana, 2015. In: Emerging infectious diseases 22 (12) 2209–2211
  Asante, Ivy Asantewaa; Bertram, Stephanie; Awuni, Joseph; Commey, Abraham Nii Okai; Aniwa, Ben; Ampofo, William Kwabena; Gabriel, Gülsah
  
• (2017) H7N9 Influenza A Virus Exhibits Importin-α7–Mediated Replication in the Mammalian Respiratory Tract. The American Journal of Pathology, 187 (4) 831-840
  Bertram, Stephanie; Thiele, Swantje; Dreier, Carola; Resa-Infante, Patricia; Preuß, Annette; van Riel, Debby; Mok, Chris K. P.; Schwalm, Folker; Peiris, Joseph S. M.; Klenk, Hans-Dieter; Gabriel, Gülsah