Coinfection of human lung epithelial cells (A549) with Influenza A virus (red) and Staphylococcus aureus (green)
© A. van Krüchten

    The role of MAPK pathways in influenza virus replication and bacterial super-infection

    Influenza viruses are barrier breaking pathogens that exploit cellular pathways to promote their replication. We have identified the Raf/MEK/ERK MAPK pathway to play a crucial role in virus replication and showed that this dependency could be used for a novel anti-influenza approach using MEK inhibitors. In the new funding period, we will not only further study the role of the pathway in ERK-mediated vRNP nuclear export but also explore a newly identified contribution of immunomodulatory activity of MEK inhibitors to prevent virus and even super-infecting bacteria from breaking the immune barrier against infections.

    Research area: Molecular virology, signalling

    Prof. Dr. rer. nat. Stephan Ludwig
    Prof. Dr. rer. nat. Christina Ehrhardt (07/2016 - 06/2020)
    Dr. Yvonne Börgeling (07/2020 - 06/2024)

    Funding period: July 2012 - June 2024

    • Publications

      Original articles

      • 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
      • 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 C, Ludwig 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.