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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:

  • Sci Immunol. 2019 Oct 25;4(40). pii: eaau4643. doi: 10.1126/sciimmunol.aau4643.

Influenza restriction factor MxA functions as inflammasome sensor in the respiratory epithelium.

Lee S, Ishitsuka A, Noguchi M, Hirohama M, Fujiyasu Y, Petric PP, Schwemmle M, Staeheli P, Nagata K, Kawaguchi A.

PubMed

  • Adv Virol. 2019 Mar 19;2019:8512363. doi: 10.1155/2019/8512363. eCollection 2019.

Poly-ADP Ribosyl Polymerase 1 (PARP1) Regulates Influenza A Virus Polymerase.

Westera L, Jennings AM, Maamary J, Schwemmle M, García-Sastre A, Bortz E.

PubMed

  • Nat Immunol. 2019 Apr;20(4):493-502. doi: 10.1038/s41590-019-0323-3. Epub 2019 Mar 4.

A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.

Hubel P, Urban C, Bergant V, Schneider WM, Knauer B, Stukalov A, Scaturro P, Mann A, Brunotte L, Hoffmann HH, Schoggins JW, Schwemmle M, Mann M, Rice CM, Pichlmair A.

PubMed

  • J Virol. 2019 Feb 5;93(4). pii: e01861-18. doi: 10.1128/JVI.01861-18. Print 2019 Feb 15.

Packaging of the Influenza Virus Genome Is Governed by a Plastic Network of RNA- and Nucleoprotein-Mediated Interactions.

Bolte H, Rosu ME, Hagelauer E, García-Sastre A, Schwemmle M.

PubMed

  • J Virol. 2019 Jan 4;93(2). pii: e00997-18. doi: 10.1128/JVI.00997-18.

Eurasian Avian-Like Swine Influenza A Viruses Escape Human MxA Restriction through Distinct Mutations in Their Nucleoprotein

Dornfeld D, Petric PP, Hassan E, Zell R, Schwemmle M.

PubMed

  • Mol Cell Proteomics2018 Oct;17(10):1909-1921. doi: 10.1074/mcp.RA117.000364. Epub 2018Jul 6.

Influenza A Virus Induces Autophagosomal Targeting of Ribosomal Proteins.

Becker AC, Gannagé M, Giese S, Hu Z, Abou-Eid S, Roubaty C, Paul P, Bühler L, Gretzmeier C, Dumit VI, Kaeser-Pebernard S, Schwemmle M, Münz C, Dengjel J.

PubMed

  • J Virol. 2018 Jul 31;92(16). piie00343-18. doi10.1128/JVI.00343-18 Print 2018 Aug 15.

Partial Inactivation of the Chromatin Remodelers SMARCA2 and SMARCA4 in Virus-Infected Cells by Caspase-Mediated Cleavage.

Dudek AH, Pfaff F, Bolte H, Waguia Kontchou C, Schwemmle M.

PubMed

  • Sci Rep. 2018 May 14;8(1):7782. doi: 10.1038/s41598-018-25858-y.

Author Correction: SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses.

Dornfeld D, Dudek AH, Vausselin T, Günther SC, Hultquist JF, Giese S, Khokhlova-Cubberley D, Chew YC, Pache L, Krogan NJ, Garcia-Sastre A, Schwemmle M, Shaw ML.

PubMed

  • Sci Rep. 2018 Feb 1;8(1):2092. doi: 10.1038/s41598-018-20458-2.

SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses.

Dornfeld D, Dudek AH, Vausselin T, Günther SC, Hultquist JF, Giese S, Khokhlova-Cubberley D, Chew YC, Pache L, Krogan NJ, Garcia-Sastre A, Schwemmle M, Shaw ML.

PubMed

  • J Virol. 2018 Mar 14;92(7). pii: e02021-17. doi: 10.1128/JVI.02021-17. Print 2018 Apr 1.

Specific Mutations in the PB2 Protein of Influenza A Virus Compensate for the Lack of Efficient Interferon Antagonism of the NS1 Protein of Bat Influenza A-Like Viruses.

Aydillo T, Ayllon J, Pavlisin A, Martinez-Romero C, Tripathi S, Mena I, Moreira-Soto A, Vicente-Santos A, Corrales-Aguilar E, Schwemmle M, García-Sastre A.

PubMed

  • Nat Commun. 2017 Nov 2;8(1):1259. doi: 10.1038/s41467-017-01112-3.

Role of influenza A virus NP acetylation on viral growth and replication.

Giese S, Ciminski K, Bolte H, Moreira ÉA, Lakdawala S, Hu Z, David Q, Kolesnikova L, Götz V, Zhao Y, Dengjel J, Chin YE, Xu , Schwemmle M.

PubMed

  • J Exp Med. 2017 May 1;214(5):1239-1248. doi: 10.1084/jem.20161033. Epub 2017 Apr 10.

In vivo evasion of MxA by avian influenza viruses requires human signature in the viral nucleoprotein.
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.
PubMed

  • Viruses. 2016 Jun 17;8(6). pii: E165. doi: 10.3390/v8060165. Review.

The Feat of Packaging Eight Unique Genome Segments.

Giese S, Bolte H, Schwemmle M.
PubMed

  • Sci Rep. 2016 Mar 18;6:23138. doi: 10.1038/srep23138.

Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import.

Götz V, Magar L, Dornfeld D, Giese S, Pohlmann A, Höper D, Kong BW, Jans DA, Beer M, Haller O, Schwemmle M.
PubMed

  • J Virol. 2015 Feb;89(4):2241-52. doi: 10.1128/JVI.02406-14. Epub 2014 Dec 10.

The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA.
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.
PubMed

  • Trends Microbiol. 2015 Mar;23(3):154-63. doi: 10.1016/j.tim.2014.12.003. Epub 2015 Jan 6. Review.

Mx GTPases: dynamin-like antiviral machines of innate immunity.

Haller O, Staeheli P, Schwemmle M, Kochs G.
PubMed

  • Cell Host Microbe. 2015 Mar 11;17(3):309-19. doi: 10.1016/j.chom.2015.01.005.

Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I.
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.
PubMed

  • J Virol. 2014 Jan;88(1):263-71. doi: 10.1128/JVI.01495-13. Epub 2013 Oct 23.

Adaptive mutations in the nuclear export protein of human-derived H5N1 strains facilitate a polymerase activity-enhancing conformation.

Reuther, P., Giese, S., Götz, V., Kilb, N., Mänz, B., Brunotte, L., Schwemmle, M.
PubMed

  • J Virol. 2013 Jul;87(13):7200-9. doi: 10.1128/JVI.00980-13. Epub 2013 Apr 24. Review.

Adaptation of avian influenza A virus polymerase in mammals to overcome the host species barrier.

Mänz B, Schwemmle M, Brunotte L.
PubMed

  • PLoS Pathog. 2013 Mar;9(3):e1003279. doi: 10.1371/journal.ppat.1003279. Epub 2013 Mar 28.

Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein.

Mänz B, Dornfeld D, Götz V, Zell R, Zimmermann P, Haller O, Kochs G, Schwemmle M.

PubMed

  • Nat Commun 3: 802 (2012)

Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells
Mänz, B., Brunotte, L., Reuther, P., Schwemmle, M.
PubMed

  • J Vis Exp 64: pii4028 (2012)

Affinity purification of influenza virus ribonucleinprotein complexes from the chromatin of infected cells
Chase, G., Schwemmle, M.
PubMed

  • PLoS Pathog 7: e1002187 (2011)

Influenza Virus Ribonucleoprotein Complexes Gain Preferential Access to Cellular Export Machinery through Chromatin Targeting
Chase, G., Rameix-Welti, M.A., Zivirbliene, A., Zvirblis, G., Götz, V., Wolff, T., Naffakh, N., Schwemmle, M.
PubMed

  • PLoS One 6: e23368 (2011)

Influenza Virus Infection Induces the Nuclear Relocalization of the Hsp99 Co-Chaperone p23 and Inhibits the Glucocorticoid Receptor Response
Ge, X., Rameix-Welti, M.A., Gault, E., Chase, G., Dos Santos Afonso, E., Picard, D., Schwemmle, M., Naffakh, N.
PubMed

  • J Virol 85:10691-10698 (2011)

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

Bogs, J., Kalthoff, D., Veits, J., Pavlova, S., Schwemmle, M., Mänz, B., Mettenleiter, T., Stech, J

PubMed

  • MBio 2: e00151-11 (2011)

Host- and Strain-Specific Regulation of Influenza Virus Polymerase Activity by Interacting Cellular Proteins

Bortz, E., Westera, L., Maamary, J., Steel, J., Albrecht, R.A., Manicassamy, B., Chase, G., Martínez-Sobrido, L., Schwemmle, M., García-Sastre, A.
PubMed

  • J Virol 85: 5228-5231 (2011)

The Influenza A Virus NS1 Protein Interacts with the Nucleoprotein of Viral Ribonucleoprotein Complexes

Robb, N.C., Chase, G., Bier, K., Vreede, F.T., Shaw, P.C., Naffakh, N., Schwemmle, M., Fodor, E.

PubMed

  • J Virol. 2011 Aug;85(16):8133-40. doi: 10.1128/JVI.00712-11. Epub 2011 Jun 15.

The viral nucleoprotein determines Mx sensitivity of influenza A viruses.

Zimmermann P, Mänz B, Haller O, Schwemmle M, Kochs G.

PubMed

  • J Biol Chem. 2011 Mar 11;286(10):8414-24. doi: 10.1074/jbc.M110.205534. Epub 2010 Dec 23.

Disruption of the viral polymerase complex assembly as a novel approach to attenuate influenza A virus.

Mänz B, Götz V, Wunderlich K, Eisel J, Kirchmair J, Stech J, Stech O, Chase G, Frank R, Schwemmle M.

PubMed

  • Antimicrob Agents Chemother. 2011 Feb;55(2):696-702. doi: 10.1128/AAC.01419-10. Epub 2010 Dec 6.

Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase.

Wunderlich K, Juozapaitis M, Ranadheera C, Kessler U, Martin A, Eisel J, Beutling U, Frank R, Schwemmle M.

PubMed

  • J Gen Virol.2010 Nov;91(Pt 11):2782-93.doi:10.1099/vir.0.023978-0. Epub 2010 Jul 14.

Fusion-active glycoprotein G mediates the cytotoxicity of vesicular stomatitis virus M mutants lacking host shut-off activity.

Hoffmann M, Wu YJ, Gerber M, Berger-Rentsch M, Heimrich B, Schwemmle M, Zimmer G.

PubMed

  • J Biol Chem. 2010 May 28;285(22):16704-12. doi: 10.1074/jbc.M110.102533. Epub 2010 Apr 2.

Limited compatibility of polymerase subunit interactions in influenza A and B viruses.

Wunderlich K, Juozapaitis M, Mänz B, Mayer D, Götz V, Zöhner A, Wolff T, Schwemmle M, Martin A.

PubMed

  • J Virol 84: 8316-8321 (2010)

A Polymorphism in the Hemagglutinin of the Human Isolates of a Highly Pathogenic H5N1 Influenza Virus Determines Organ Tropism in Mice

Mänz, B., Matrosovich, M., Bovin, N., Schwemmle, M.

PubMed

  • J Virol. 2010 Jun;84(11):5670-7. doi: 10.1128/JVI.00272-10. Epub 2010 Mar 24.

Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections.

Mordstein M, Neugebauer E, Ditt V, Jessen B, Rieger T, Falcone V, Sorgeloos F, Ehl S, Mayer D, Kochs G, Schwemmle M, Günther S, Drosten C, Michiels T, Staeheli P.

PubMed

  • PLoS One. 2009 Oct 20;4(10):e7517. doi: 10.1371/journal.pone.0007517.

Identification of a PA-binding peptide with inhibitory activity against influenza A and B virus replication.

Wunderlich K, Mayer D, Ranadheera C, Holler AS, Mänz B, Martin A, Chase G, Tegge W, Frank R, Kessler U, Schwemmle M.

PubMed

  • J Virol. 2008 Nov;82(22):11446-53. doi: 10.1128/JVI.01284-08. Epub 2008 Sep 3.

The interferon antagonist ML protein of thogoto virus targets general transcription factor IIB.

Vogt C, Preuss E, Mayer D, Weber F, Schwemmle M, Kochs G.

PubMed

  • Virol 377: 431-439 (2008)

Hsp90 inhibitors reduce influenza virus replication in cell culture
Chase, G., Deng, T., Fodor, E., Leung, B., Mayer, D., Schwemmle, M., Brownlee, G.
PubMed

  • J Virol. 2007 Jul;81(14):7801-4. Epub 2007 May 9.

Peptide-mediated interference with influenza A virus polymerase.

Ghanem A, Mayer D, Chase G, Tegge W, Frank R, Kochs G, García-Sastre A, Schwemmle M.

PubMed

  • J Proteome Res 6: 672-82 (2007)

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

  • Proteomics. 2005 Nov;5(17):4483-7.

Isolation of viral ribonucleoprotein complexes from infected cells by tandem affinity purification.

Mayer D, Baginsky S, Schwemmle M.

PubMed

  •  

  • Am J Pathol. 2002 Nov;161(5):1749-59.

Guanylate-binding protein-1 expression is selectively induced by inflammatory cytokines and is an activation marker of endothelial cells during inflammatory diseases.

Lubeseder-Martellato C, Guenzi E, Jörg A, Töpolt K, Naschberger E, Kremmer E, Zietz C, Tschachler E, Hutzler P, Schwemmle M, Matzen K, Grimm T, Ensoli B, Stürzl M.

PubMed

  • EMBO J. 2001 Oct 15;20(20):5568-77.

The helical domain of GBP-1 mediates the inhibition of endothelial cell proliferation by inflammatory cytokines.

Guenzi E, Töpolt K, Cornali E, Lubeseder-Martellato C, Jörg A, Matzen K, Zietz C, Kremmer E, Nappi F, Schwemmle M, Hohenadl C, Barillari G, Tschachler E, Monini P, Ensoli B, Stürzl M.

PubMed

  • J Mol Biol. 1999 Sep 17;292(2):321-32.

Nucleotide-binding characteristics of human guanylate-binding protein 1 (hGBP1) and identification of the third GTP-binding motif.

Praefcke GJ, Geyer M, Schwemmle M, Robert Kalbitzer H, Herrmann C.

PubMed

  • J Leukoc Biol. 1996 Sep;60(3):423-31.

Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1.

Nantais DE, Schwemmle M, Stickney JT, Vestal DJ, Buss JE.

PubMed

  • FEBS Lett. 1996 Jul 15;390(1):69-72.

GTPase properties of the interferon-induced human guanylate-binding protein 2.

Neun R, Richter MF, Staeheli P, Schwemmle M.

PubMed

  • J Biol Chem. 1996 Apr 26;271(17):10304-8.

Chicken guanylate-binding protein. Conservation of GTPase activity and induction by cytokines.

Schwemmle M, Kaspers B, Irion A, Staeheli P, Schultz U.

PubMed

 

 

 

 


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  •  J Autoimmun. 1995 Dec;8(6):825-42. 

Activation of a murine autoreactive B cell by immunization with human recombinant autoantigen La/SS-B: characterization of the autoepitope.

Tröster H1, Bartsch H, Klein R, Metzger TE, Pollak G, Semsei I, Schwemmle M, Pruijn GJ, van Venrooij WJ, Bachmann M.

PubMed

  •  J Biol Chem. 1995 Jun 2;270(22):13518-23. 

Unexpected structural requirements for GTPase activity of the interferon-induced MxA protein.

Schwemmle M1, Richter MF, Herrmann C, Nassar N, Staeheli P.

PubMed

  •  J Biol Chem. 1995 Jun 2;270(22):13512-7. 

Interferon-induced MxA protein. GTP binding and GTP hydrolysis properties.

Richter MF, Schwemmle M, Herrmann C, Wittinghofer A, Staeheli P.

PubMed

  •  Exp Cell Res. 1995 May;218(1):17-27. 

Nuclear localization of the interferon-inducible protein kinase PKR in human cells and transfected mouse cells.

Jeffrey IW1, Kadereit S, Meurs EF, Metzger T, Bachmann M, Schwemmle M, Hovanessian AG, Clemens MJ.

PubMed

  •  J Mol Endocrinol. 1995 Apr;14(2):209-26. 

Contribution of a 12 kDa protein to the angiotensin II-induced stabilization of angiotensinogen mRNA: interaction with the 3' untranslated mRNA.

Klett C, Bader M, Schwemmle M, Ganten D, Hackenthal E.

PubMed

  •  Anal Biochem. 1995 Mar 1;225(2):366-8. 

A possible cloning artifact occurring frequently during unidirectional cDNA cloning in the uni-ZAP XR vector system.

Tröster H1, Semsei I, Schwemmle M, Müller WE, Bachmann M.

PubMed

  •  Virology. 1995 Jan 10;206(1):545-54. 

Vesicular stomatitis virus transcription inhibited by purified MxA protein.

Schwemmle M, Weining KC, Richter MF, Schumacher B, Staeheli P.

PubMed

  •  J Exp Med. 1994 Dec 1;180(6):2059-67. 

One gene, two transcripts: isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary Sjögrens' syndrome.

Tröster H, Metzger TE, Semsei I, Schwemmle M, Winterpacht A, Zabel B, Bachmann M.

PubMed

  •  J Biol Chem. 1994 Apr 15;269(15):11299-305. 

The interferon-induced 67-kDa guanylate-binding protein (hGBP1) is a GTPase that converts GTP to GMP.

Schwemmle M, Staeheli P.

PubMed

  •  J Virol. 1993 Nov;67(11):6726-32. 

A functional GTP-binding motif is necessary for antiviral activity of Mx proteins.

Pitossi F, Blank A, Schröder A, Schwarz A, Hüssi P, Schwemmle M, Pavlovic J, Staeheli P.

PubMed

  •  Nucleic Acids Res. 1993 Sep 25;21(19):4483-90. 

Comparative analysis of the regulation of the interferon-inducible protein kinase PKR by Epstein-Barr virus RNAs EBER-1 and EBER-2 and adenovirus VAI RNA.

Sharp TV, Schwemmle M, Jeffrey I, Laing K, Mellor H, Proud CG, Hilse K, Clemens MJ.

PubMed

  •  Gene. 1993 Apr 30;126(2):265-8. 

Isolation of rat cDNA clones coding for the autoantigen SS-B/La: detection of species-specific variations.

Semsei I, Tröster H, Bartsch H, Schwemmle M, Igloi GL, Bachmann M.

PubMed

  •  Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10292-6. 

Localization of Epstein-Barr virus-encoded RNAs EBER-1 and EBER-2 in interphase and mitotic Burkitt lymphoma cells.

Schwemmle M, Clemens MJ, Hilse K, Pfeifer K, Tröster H, Müller WE, Bachmann M.

PubMed

  •  Eur J Biochem. 1991 Oct 1;201(1):139-45. 

A 60-kDa protein from rabbit reticulocytes specifically recognizes the capped 5' end of beta-globin mRNA.

Schwemmle M1, Schickinger J, Bader M, Sarre TF, Hilse K.

pubmed

  •  Nucleic Acids Res. 1991 Jan 25;19(2):243-8. 

Binding of Epstein-Barr virus small RNA EBER-1 to the double-stranded RNA-activated protein kinase DAI.

Clarke PA, Schwemmle M, Schickinger J, Hilse K, Clemens MJ.

PubMed

  •  Mol B iol Rep. 1990;14(2-3):77-8. 

A 60 kDa protein from rabbit reticulocytes binds specifically to (part of) the leader sequence of beta-globin mRNA in a cap dependent manner.

Schwemmle M, Schickinger J, Bader M, Sarre TF, Hilse K.

PubMed

  • Eur J Biochem. 1989 Oct 1;184(3):589-96.

Binding of globin mRNA, beta-globin mRNA segments and RNA homopolymers by immobilized protein of polysomal globin messenger ribonucleoprotein.

Görlach M, Hermann M, Schwemmle M, Hilse K.

PubMed

  • FEBS Lett. 1989 Jul 17;251(1-2):117-20.

Binding of mRNA by an oligopeptide containing an evolutionarily conserved sequence from RNA binding proteins.

Schwemmle M, Görlach M, Bader M, Sarre TF, Hilse K.

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