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Institute of Virology

Adaptation processes of avian influenza viruses required to cross the species barrier

Highly pathogenic avian H5N1 or H7N9 viruses can infect humans and cause severe diseases. However efficient human-to-human transmission has not been observed to date, indicating an incomplete adaptation. It is believed that the mutations required for adaptation can occur within the infected human host by a selection process of minor virus variants. In addition to such adaptation processes, successful infection is dependent on direct interactions of viral proteins with host-cell proteins. The goal of this project is to study the functional consequences of the mutations acquired in the human host and to identify host-cell factors that are essential for viral replication. We also want to study adaptation processes of influenza A viruses to cellular host restriction factors such as the antivirally active Mx GTPases. With these studies we hope to gain more insights in the adaptation potential of highly pathogenic H5N1 or H7N9 viruses.

Amino acid positions of NP mediating Mx resistance.Positions of adaptive mutations required for Mx resistance of the 1918 (left panel, marked in blue) and the pH1N1 NP (right panel, marked in red). Amino acids that exhibit only minor contribution to Mx resistance are highlighted in light red. See also: Mänz et al. PlosPathogen 2013.


Selected References:

  1. Mayer, D., Molawi, K., Martínez-Sobrido, L., Ghanem, A., Thomas, St., Baginsky S., Grossmann J., García-Sastre, A., Schwemmle, M.
    Identification of cellular interaction partners of the influenza virus ribonucleoprotein complex and polymerase complex using proteomic-based approaches

    J Proteome Res 6: 672-82 (2007)
    >PubMed
  2. Chase, G., Deng, T., Fodor, E., Leung, B., Mayer, D., Schwemmle, M., Brownlee, G.
    Hsp90 inhibitors reduce influenza virus replication in cell culture
    Virol 377: 431-439 (2008)
    >PubMed
  3. Mänz, B., Matrosovich, M., Bovin, N., Schwemmle, M.
    A Polymorphism in the Hemagglutinin of the Human Isolates of a Highly Pathogenic H5N1 Influenza Virus Determines Organ Tropism in Mice
    J Virol 84: 8316-8321 (2010)
    >PubMed
  4. Robb, N.C., Chase, G., Bier, K., Vreede, F.T., Shaw, P.C., Naffakh, N., Schwemmle, M., Fodor, E.
    The Influenza A Virus NS1 Protein Interacts with the Nucleoprotein of Viral Ribonucleoprotein Complexes
    J Virol 85: 5228-5231 (2011)
    >PubMed
  5. Bortz, E., Westera, L., Maamary, J., Steel, J., Albrecht, R.A., Manicassamy, B., Chase, G., Martínez-Sobrido, L., Schwemmle, M., García-Sastre, A.
    Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins
    MBio 2: e00151-11 (2011)
    >PubMed
  6. Bogs, J., Kalthoff, D., Veits, J., Pavlova, S., Schwemmle, M., Mänz, B., Mettenleiter, T., Stech, J.
    Reversion of PB2-627E to -627K during Replication of an H5N1 Clade 2.2 Virus in Mammalian Hosts Depends on the Origin of the Nucleoprotein
    J Virol 85:10691-10698 (2011)
    >PubMed
  7. Ge, X., Rameix-Welti, M.A., Gault, E., Chase, G., Dos Santos Afonso, E., Picard, D., Schwemmle, M., Naffakh, N.
    Influenza Virus Infection Induces the Nuclear Relocalization of the Hsp99 Co-Chaperone p23 and Inhibits the Glucocorticoid Receptor Response
    PLoS One 6: e23368 (2011)
    >PubMed
  8. Chase, G., Rameix-Welti, M.A., Zivirbliene, A., Zvirblis, G., Götz, V., Wolff, T., Naffakh, N., Schwemmle, M.
    Influenza Virus Ribonucleoprotein Complexes Gain Preferential Access to Cellular Export Machinery through Chromatin Targeting
    PLoS Pathog 7: e1002187 (2011)
    >PubMed
  9. Chase, G., Schwemmle, M.
    Affinity purification of influenza virus ribonucleinprotein complexes from the chromatin of infected cells
    J Vis Exp 64: pii4028 (2012)
    >PubMed
  10. Mänz, B., Brunotte, L., Reuther, P., Schwemmle, M.
    Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells
    Nat Commun 3: 802 (2012)
    >PubMed
  11. Reuther, P., Giese, S., Götz, V., Kilb, N., Mänz, B., Brunotte, L., Schwemmle, M.
    Adaptive mutations in the nuclear export protein of human-derived H5N1 strains facilitate a polymerase activity-enhancing conformation.
    J Virol. 2014 Jan;88(1):263-71. doi: 10.1128/JVI.01495-13. Epub 2013 Oct 23.
    >PubMed
  12. Mänz B, Schwemmle M, Brunotte L.
    Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier.
    J Virol. 2013 Jul;87(13):7200-9. doi: 10.1128/JVI.00980-13. Epub 2013 Apr 24. Review.
    >PubMed
  13. Mänz B, Dornfeld D, Götz V, Zell R, Zimmermann P, Haller O, Kochs G, Schwemmle M.
    Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.
    PLoS Pathog. 2013 Mar;9(3):e1003279. doi: 10.1371/journal.ppat.1003279. Epub 2013 Mar 28.
    >PubMed
  14. Weber M, Sediri H, Felgenhauer U, Binzen I, Bänfer S, Jacob R, Brunotte L, García-Sastre A, Schmid-Burgk JL, Schmidt T, Hornung V, Kochs G, Schwemmle M, Klenk HD, Weber F.
    Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I.
    Cell Host Microbe. 2015 Mar 11;17(3):309-19. doi: 10.1016/j.chom.2015.01.005.
    >PubMed
  15. Haller O, Staeheli P, Schwemmle M, Kochs G.
    Mx GTPases: dynamin-like antiviral machines of innate immunity.
    Trends Microbiol. 2015 Mar;23(3):154-63. doi: 10.1016/j.tim.2014.12.003. Epub 2015 Jan 6. Review.
    >PubMed
  16. Riegger D, Hai R, Dornfeld D, Mänz B, Leyva-Grado V, Sánchez-Aparicio MT, Albrecht RA, Palese P, Haller O, Schwemmle M, García-Sastre A, Kochs G, Schmolke M.
    The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA.
    J Virol. 2015 Feb;89(4):2241-52. doi: 10.1128/JVI.02406-14. Epub 2014 Dec 10.
    >PubMed
  17. Götz V, Magar L, Dornfeld D, Giese S, Pohlmann A, Höper D, Kong BW, Jans DA, Beer M, Haller O, Schwemmle M.
    Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import.
    Sci Rep. 2016 Mar 18;6:23138. doi: 10.1038/srep23138.
    >PubMed
  18. Giese S, Bolte H, Schwemmle M.
    The Feat of Packaging Eight Unique Genome Segments.
    Viruses. 2016 Jun 17;8(6). pii: E165. doi: 10.3390/v8060165. Review.
    >PubMed
  19. Deeg CM, Hassan E, Mutz P, Rheinemann L, Götz V, Magar L, Schilling M, Kallfass C, Nürnberger C, Soubies S, Kochs G, Haller O, Schwemmle M, Staeheli P.
    In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein.
    J Exp Med. 2017 May 1;214(5):1239-1248. doi: 10.1084/jem.20161033. Epub 2017 Apr 10.
    >PubMed

Institut für Virologie

Hermann-Herder-Strasse 11
D-79104 Freiburg

Ärztlicher Direktor

Prof. Dr. med. Hartmut Hengel
hartmut.hengel@uniklinik-freiburg.de

Team Leader:

Martin Schwemmle
(Ph.D., Professor)
Phone: +49 761 203 6526
Fax: +49 761 203 6639