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

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

    Invasion of influenza viruses (IV) and/or Staphylococcus aureus into cells of epithelial and endothelia barriers results in the activation of the Raf/MEK/ERK kinase cascade. It was previously shown that active ERK promotes nuclear export of IV genomes thereby supporting viral replication. The detailed mechanisms will now be further elucidated. Furthermore, regulation and function of the ERK pathway upon IV and/or S. aureus infection will be explored with respect to changes in immune responses, inflammation and pathogen load. Finally, suitability of the pathway as a target for anti-pathogen therapy will be evaluated.

    Research area: Molecular virology, signalling

    Prof. Dr. rer. nat. Stephan Ludwig
    Prof. Dr. rer. nat. Christina Ehrhardt (until June 2020)
    Dr. Yvonne Börgeling (since July 2020)

    Funding period: July 2012 - June 2024

    • Publications

      Original articles

      • 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.