The Role of the Nuclear Import Machinery in the Adaptation of Avian Influenza A Viruses to the Mammalian Host
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
(See online at https://doi.org/10.1128/jvi.00270-14) - (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.
(See online at https://doi.org/10.1128/jvi.00665-15) - (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
(See online at https://doi.org/10.1093/infdis/jiv240) - (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
(See online at https://doi.org/10.1128/jvi.00583-15) - (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
(See online at https://doi.org/10.1038/ncomms1158) - (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
(See online at https://doi.org/10.1371/journal.ppat.1002488) - (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
(See online at https://doi.org/10.1038/srep28583) - (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
(See online at https://doi.org/10.3201/eid2212.160639) - (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
(See online at https://doi.org/10.1016/j.ajpath.2016.12.017)
