Die Rolle von MAPK Signalwegen in der Influenza Virus Replikation und bakteriellen Super-Infektion

    Influenzaviren sind Barriere-brechende Krankheitserreger, die zelluläre Signalwege ausnutzen, um ihre Replikation zu fördern. Wir haben die Raf/MEK/ERK MAPK Kaskade als entscheidend für die Virusreplikation identifiziert, was zu einem neuen anti-Influenza Ansatz mit sogenannten MEK Inhibitoren geführt hat. In der neuen Förderperiode werden wir nicht nur die Rolle des Signalwegs im ERK-vermittelten vRNP-Kernexport weiter untersuchen, sondern auch den kürzlich identifizierten Beitrag der immunmodulatorischen Aktivität von MEK-Inhibitoren für die antivirale und sogar antibakterielle Wirkung studieren.

    Forschungsgebiet: Molekulare Virologie, Signalübertragung

    Prof. Dr. rer. nat. Stephan Ludwig
    Prof. Dr. rer. nat. Christina Ehrhardt   (07/2012 - 06/2020)
    Dr. rer. nat. Yvonne Börgeling              (07/2020 - 06/2024)

    Projektlaufzeit: Juli 2012 - Juni 2024

    • Publikationen

      Originalartikel

      • Kleinehr J, Schöfbänker M, Daniel K, Günl F, Mohamed FF, Janowski J, Brunotte L, Boergeling Y, Liebmann M, Behrens M, Gerdemann A, Klotz L, Esselen M, Humpf HU, Ludwig S, Hrincius ER (2023) Glycolytic interference blocks influenza A virus propagation by impairing viral polymerase-driven synthesis of genomic vRNA. PLoS Pathog. 19(7):e1010986. doi:10.1371/journal.ppat.1010986
      • Ludwig S, Pleschka S, Planz O (2023) MEK inhibitors as novel host-targeted antivirals with a dual-benefit mode of action against hyperinflammatory respiratory viral diseases.  Curr Opin Virol 59: 101304.  doi:10.1016/j.coviro.2023.101304.
      • Schloer S, Treuherz D, Faist A, de Witt M, Wunderlich K, Wiewrodt R, Wiebe K, Barth P, Wälzlein JH, Kummer S, Balkema-Buschmann A, Ludwig S, Brunotte L, Rescher U (2022) 3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases. Emerg Microbes Infect. 11(1):2160-2175. doi:10.1080/22221751.2022.2117101
      • Schreiber A, Ambrosy B, Planz O, Schloer S, Rescher U, Ludwig S (2022) The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs. Pharmaceutics 14(9): 1776. doi:10.3390/pharmaceutics14091776
      • Schreiber A, Viemann D, Schöning J, Schloer S, Mecate Zambrano A, Brunotte L, Faist A, Schöfbänker M, Hrincius E, Hoffmann H, Hoffmann M, Pöhlmann S, Rescher U, Planz O, Ludwig S (2022) The MEK1/2-inhibitor ATR-002 efficiently blocks SARS-CoV-2 propagation and alleviates pro-inflammatory cytokine/chemokine responses. Cell Mol Life Sci. 79(1):65. doi:10.1007/s00018-021-04085-1
      • Wixler V, Zaytsev IZ, Leite Dantas R, Schied T, Boergeling Y, Lührmann V, Varga G, Masemann D, Ludwig S (2022) Small spleen peptides prevent development of psoriatic arthritis via restoration of peripheral tolerance. Mol Ther. 30(2):745-762. doi:10.1016/j.ymthe.2021.08.030
      • Brunotte L, Zheng S, Mecate-Zambrano A, Tang J, Ludwig S, Rescher U, Schloer S. (2021) Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro. Pharmaceutics. 13(9):1400. doi:10.3390/pharmaceutics13091400
      • Deinhardt-Emmer S, Jäckel L, Häring C, Böttcher S, Wilden JJ, Glück B, Heller R, Schmidtke M, Koch M, Löffler B, Ludwig S, Ehrhardt C (2021) Inhibition of Phosphatidylinositol 3-Kinase by Pictilisib Blocks Influenza Virus Propagation in Cells and in Lungs of Infected Mice. Biomolecules 11(6): 808. doi:10.3390/biom11060808.
      • Del Sarto J, Gerlt V, Friedrich ME, Anhlan D, Wixler V, Teixeira MM, Boergeling Y, Ludwig S (2021) Phosphorylation of JIP4 at S730 Presents Antiviral Properties against Influenza A Virus Infection.  J Virol 95(20): e0067221. doi:10.1128/JVI.00672-21.
      • Kleinehr J, Wilden JJ, Boergeling Y, Ludwig S, Hrincius ER (2021) Metabolic Modifications by Common Respiratory Viruses and Their Potential as New Antiviral Targets. Viruses. 13(10):2068. doi:10.3390/v13102068
      • Nacken W, Schreiber A, Masemann D, Ludwig S (2021) The Effector Domain of the Influenza A Virus Nonstructural Protein NS1 Triggers Host Shutoff by Mediating Inhibition and Global Deregulation of Host Transcription When Associated with Specific Structures in the Nucleus. mBio 12(5): e0219621. doi:10.1128/mBio.02196-21.
      • Schloer S, Brunotte L, Mecate-Zambrano A, Zheng S, Tang J, Ludwig S, Rescher U (2021) Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharmacol. 178(11): 2339-2350. doi:10.1111/bph.15418.
      • Wilden JJ, Jacob JC, Ehrhardt C, Ludwig S, Boergeling Y (2021) ltered Signal Transduction in the Immune Response to Influenza Virus and S. pneumoniae or S. aureus Co-Infections. Int J Mol Sci 22(11): 5486. doi:10.3390/ijms22115486.
      • Boff L, Schreiber A, da Rocha Matos A, Del Sarto J, Brunotte L, Munkert J, Melo Ottoni F, Silva Ramos G, Kreis W, Castro Braga F, José Alves R, Maia de Pádua R, Maria Oliveira Simões C, Ludwig S (2020) Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation. Molecules. 25(20):4853. doi:10.3390/molecules25204853
      • Laure M, Hamza H, Koch-Heier J, Quernheim M, Müller C, Schreiber A, Müller G, Pleschka S, Ludwig S, Planz O (2020) Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model. Antiviral Research 178: 104806. doi: 10.1016/j.antiviral.2020.104806.
      • Leite Dantas R, Bettenworth D, Varga G, Weinhage T, Wami HT, Dobrindt U, Roth J, Vogl T, Ludwig S, Wixler V. (2020) Spontaneous onset of TNFα-triggered colonic inflammation depends on functional T lymphocytes, S100A8/A9 alarmins, and MHC H-2 haplotype. J Pathol 251(4):388-399
      • Masemann D, Ludwig S, Börgeling Y (2020) Advances in Transgenic Mouse Models to Study Infections by Human Pathogenic Viruses. nt J Mol Sci. 21(23):9289. doi:10.3390/ijms21239289
      • Schloer S, Brunotte L, Goretzko J, Mecate-Zambrano A, Korthals N, Gerke V, Ludwig S, Rescher U (2020) Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg Microbes Infect. 9(1):2245-2255. doi:10.1080/22221751.2020.1829082
      • Schloer S, Goretzko J, Pleschka S, Ludwig S, Rescher U (2020) Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection. Viruses. 12(7):703. doi:10.3390/v12070703
      • Schreiber A, Boff L, Anhlan D, Krischuns T, Brunotte L, Schuberth C, Wedlich-Söldner R, Drexler H, Ludwig S (2020) Dissecting the mechanism of signaling-triggered nuclear export of newly synthesized influenza virus ribonucleoprotein complexes. Proc Natl Acad Sci U S A. 117(28):16557-16566. doi:10.1073/pnas.2002828117
      • Schreiber, A, Liedmann, S, Brunotte, L, Anhlan, D, Ehrhardt, C, Ludwig S (2020) Type I interferon antagonistic properties of influenza B virus polymerase proteins. Cell Microbiol. 22(2):e13143. doi:10.1111/cmi.13143
      • Wilden JJ, Hrincius ER, Niemann S, Boergeling Y, Löffler B, Ludwig S, Ehrhardt C (2020) Impact of Staphylococcus aureus Small Colony Variants on Human Lung Epithelial Cells with Subsequent Influenza Virus Infection.  Microorganisms. 8(12):1998. doi:10.3390/microorganisms8121998
      • Wilden JJ, van Krüchten A, Gieselmann L, Hrincius ER, Deinhardt-Emmer S, Haupt KF, Preugschas HF, Niemann S, Ludwig S, Ehrhardt C (2020) The influenza replication blocking inhibitor LASAG does not sensitize human epithelial cells for bacterial infections. PLoS One 15(5):e0233052. doi: 10.1371/journal.pone.0233052.
      • Preugschas HF, Hrincius ER, Mewis C, Tran GVQ, Ludwig S, Ehrhardt C (2019) Late activation of the Raf/MEK/ERK pathway is required for translocation of the respiratory syncytial virus F protein to the plasma membrane and efficient viral replication. Cell Microbiol 21(1):e12955.
      • Schreiber A, Liedmann S, Brunotte L, Anhlan D, Ehrhardt C, Ludwig S (2019) Type I interferon antagonistic properties of influenza B virus polymerase proteins. Cell Microbiol. 11:e13143. doi: 10.1111/cmi.13143. [Epub ahead of print]
      • Schloer S, Hübel N, Masemann D, Pajonczyk D, Brunotte L, Ehrhardt C, Brandenburg LO, Ludwig S, Gerke V, Rescher U (2019a) The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murina influenza A virus infection model. FASEB J 33(11):12188-12199. doi: 10.1096/fj.201901265R.
      • Bruchhagen C, Jarick M, Mewis C, Hertlein T, Niemann S, Ohlsen K, Peters G, Planz O, Ludwig S, & Ehrhardt C (2018) Metabolic conversion of CI-1040 turns a cellular MEK-inhibitor into an antibacterial compound. Sci Rep 8: 9114-018-27445-7Klemm C, Boergeling Y, Ludwig S, & Ehrhardt C (2018) Immunomodulatory nonstructural proteins of influenza A viruses. Trends Microbiol 26: 624-636
      • Krischuns T, Gunl F, Henschel L, Binder M, Willemsen J, Schloer S, Rescher U, Gerlt V, Zimmer G, Nordhoff C, Ludwig S, & Brunotte L (2018) Phosphorylation of TRIM28 Enhances the Expression of IFN-beta and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells. Front Immunol 9: 2229
      • Nacken W, Wixler V, Ehrhardt C, & Ludwig S (2017) Influenza A virus NS1 protein-induced JNK activation and apoptosis are not functionally linked. Cell Microbiol 19: 10.1111/cmi.12721. Epub 2017 Jan 27
      • Schrader T, Dudek SE, Schreiber A, Ehrhardt C, Planz O, & Ludwig S (2018) The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression. Antiviral Res 157: 80-92
      • Van Kruchten A, Wilden JJ, Niemann S, Peters G, Löffler B, Ludwig S, & Ehrhardt C (2018) Staphylococcus aureus triggers a shift from influenza virus-induced apoptosis to necrotic cell death. FASEB J. 32: 2779-2793.
      • Haasbach E, Muller C, Ehrhardt C, Schreiber A, Pleschka S, Ludwig S, & Planz O (2017) The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo. Antiviral Res 142: 178-184
      • Holzberg M*, Boergeling Y*, Schrader T, Ludwig S, & Ehrhardt C (2017) Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways. Front Microbiol 8: 2426 *these authors contributed equally
      • Klemm C, Bruchhagen C, van Kruchten A, Niemann S, Loffler B, Peters G, Ludwig S, & Ehrhardt C (2017) Mitogen-activated protein kinases (MAPKs) regulate IL-6 over-production during concomitant influenza virus and Staphylococcus aureus infection. Sci Rep 7: 4247
      • Haasbach E, Müller C, Ehrhardt C, Schreiber A, Pleschka S, Ludwig S, Planz O. (2017). The MEK-inhibitor CI-1040 displays a broad anti-influenza virus activity in vitro and provides a prolonged treatment window compared to standard of care in vivo. Antiviral Research 142 (2017) 178e184. doi: 10.1016/j.antiviral.2017.03.024
      • Klemm C, Bruchhagen C, van Krüchten A, Niemann S, Löffler B, Peters G, Ludwig S, Ehrhardt C. (2017). Mitogen-activated protein kinases (MAPKs) regulate IL-6 over-production during concomitant influenza virus and Staphylococcus aureus infection. Sci Rep. 14;7:42473. Doi: 10.1038/srep42473
      • Leite Dantas R, Brachvogel B, Schied T, Bergmeier V, Skryabin B, Vogl T, Ludwig S, Wixler V. (2017). The LIM-Only Protein Four and a Half LIM Domain Protein 2 Attenuates Development of Psoriatic Arthritis by Blocking Adam17 Mediated Tumor Necrosis Factor Release. American Journal of Pathology. 187;11:2388. doi: 10.1016/j.ajpath.2017.07.015
      • Masemann D, Boergeling Y, Ludwig S. (2017). Employing RNA viruses to fight cancer: novel insights into oncolytic virotherapy. Biol. Chem. 2017; 398(8): 891-909 doi: 10.1515/hsz-2017-0103
      • Nacken W, Wixler V, Ehrhardt C, Ludwig S. (2017). Influenza A virus NS1 protein-induced JNK activation and apoptosis are not functionally linked. Cell Microbiol. 2017 Jul 19(7). Doi: 10.1111/cmi.12721 [Epub ahead of print]
      • Dudek SE, Nitzsche K, Ludwig S, Ehrhardt C (2016) Influenza A viruses suppress cyclooxygenase-2 expression by affecting its mRNA stability. Sci Rep 6: 27275. (doi: 10.1038/srep27275) 
      • Kathum OA, Schräder T, Anhlan D, Nordhoff C, Liedmann S, Pande A, Mellmann A, Ehrhardt C, Wixler V, Ludwig S (2016) Phosphorylation of influenza A virus NS1 protein at threonine 49 suppresses its interferon antagonistic activity. Cell Microbiol 18(6): 784–791. (doi:10.1111/cmi.12559) 
      • Silva IT, Carvalho A, Lang KL, Dudek SE, Masemann D, Durán FJ, Duran FJ, Caro MSB, Rapp UR, Wixler V, Schenkel EP, Simões CMO, Ludwig S (2015) In vitro and in vivo antitumor activity of a novel semisynthetic derivative of cucurbitacin B. PLoS ONE 10(2): e0117794. (doi:10.1371/journal.pone.0117794) 
      • Börgeling Y, Rozhdestvensky TS, Schmolke M, Resa-Infante P, Robeck T, Randau G, Wolff T, Gabriel G, Brosius J, Ludwig S (2015) Evidence for a novel mechanism of influenza virus-induced type I interferon expression by a defective RNA-encoded protein. PLoS Pathog 11: e1004924.
      • Börgeling Y, Schmolke M, Viemann D, Nordhoff C, Roth J, Ludwig S (2014) Inhibition of p38 mitogen-activated protein kinase impairs influenza virus-induced primary and secondary host gene responses and protects mice from lethal H5N1 infection. J Biol Chem 289(1): 13-27. 
      • Dierkes R, Warnking K, Liedmann S, Seyer R, Ludwig S, Ehrhardt C (2014) The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity. PloS One 9: e88520. 
      • Köther K, Nordhoff C, Masemann D, Varga G, Bream JH, Gaestel M, Wixler V, Ludwig S (2014) MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection. FASEB J 28: 4235-4246. 
      • Liedmann S, Hrincius ER, Anhlan D, McCullers JA, Ludwig S, Ehrhardt C (2014) New virulence determinants contribute to the enhanced immune response and reduced virulence of an influenza A virus A/PR8/34 variant. J Infect Dis 209: 532-541. 
      • Liedmann S, Hrincius ER, Guy C, Anhlan D, Dierkes R, Carter R, Wu G, Staeheli P, Green DR, Wolff T, McCullers JA, Ludwig S, Ehrhardt C (2014) Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions. Nature Comm 5: 5645. 
      • Nacken W, Anhlan D, Hrincius ER, Mostafa A, Wolff T, Sadewasser A, Pleschka S, Ehrhardt C, Ludwig S (2014) Activation of c-jun N-terminal kinase upon Influenza A Virus (IAV) infection is independent of pathogen related receptors, but dependent on amino acid sequence variations of the IAV NS1. J Virol 88: 8843-8852. 
      • Warnking K, Klemm C, Löffler B, Niemann S, van Krüchten A, Peters G, Ludwig S, Ehrhardt C (2014). Super-infection with Staphylococcus aureus inhibits influenza virus-induced type I IFN signalling through impaired STAT1-STAT2 dimerization. Cell Microbiol (in press). [ doi: 10.1111/cmi.12375. Epub ahead of print].
      • Nacken W, Ehrhardt CLudwig S (2012) Small molecule inhibitors of the c-Jun N-terminal kinase (JNK) possess antiviral activity against highly pathogenic avian and human pandemic influenza A viruses. Biol Chem 393: 525-534.