• Projects

Project area C:

Host response to RNA virus infection

Principal investigator:

Prof. Dr. Lienhard Schmitz

Institut für Biochemie
Justus-Liebig-Universität Gießen
Friedrichstraße 24
35392 Gießen

Phone: 0641-99 47570
E-Mail: lienhard.schmitz(at)biochemie.

Principal investigator:

Prof. Dr. Stephan Pleschka

Institut für Medizinische Virologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen

Phone: 0641-99 47750
E-Mail: stephan.pleschka(at)viro.med.uni-giessen(dot)de

Research areas: Biochemistry, Signal Transduction, Virology

Influenza A viruses are characterized by a high degree of genomic plasticity which enables them to quickly adapt to new environmental conditions and to cross species barriers, causing epidemics and occasional pandemics. In the first funding period, CRISPR-Cas9-mediated gene editing was employed to generate mouse lung epithelial cells deficient in specific key proteins of the NF-B pathway. The functional analysis of these cells revealed that NF-κB was not relevant for replication of a mouse-adapted SC35M, while the absence of NF-κB activity increased replication of the non-adapted SC35 virus. The analysis of reassortant viruses showed that the anti-viral effect of NF-B is determined by the IAV genotype. In addition, the group has identified thousands of IAV-regulated phosphorylation sites of host cell and viral proteins were identified in a phospho-proteomic screen, which led to the discovery of new IAV-regulated kinase pathways, phosphorylation motifs, and cellular processes. This first comprehensive phospho-proteomic screen now allows to study the contribution of key phosphorylation sites and newly discovered pathways for IAV replication.

Project-related publications of the investigators:
  • Poppe, M., Wittig, S., Jurida, L., Bartkuhn, M., Wilhelm, J., Müller, H., Beuerlein, K., Karl, N., Bhuju, S., Ziebuhr, J., Schmitz, M.L. and M. Kracht (2017) The NF-κB-dependent and -independent transcriptome and chromatin landscapes of coronavirus 229E-infected human cells. Plos Pathog. 13(3):e1006286.
  • Seibert, M., Krüger, M., Watson, N.A., Sen, O., Daum, J.R., Slotman, J.A., Braun, T., Houtsmuller, A.B., Gorbsky, G.J., Jacob, R., Kracht, M., Higgins, J.M.G. and M.L. Schmitz (2019) CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation. J. Cell Biol. 218, 1164-1181.
  • Weber, A., Dam, S., Saul, V.V., Kuznetsova, I., Müller, C., Fritz-Wolf, K., Becker, K., Linne, U., Gu, H., Stokes, M.P., Pleschka, S., Kracht, M. and M.L. Schmitz (2019) Phosphoproteome analysis of cells infected with adapted and non-adapted influenza A virus reveals novel pro- and antiviral signaling networks. J. Virol., 93(13). pii: e00528-19.
  • Ritter, O. and M.L. Schmitz (2019) Differential intracellular localization and dynamic nucleocytoplasmic shuttling of homeodomain-interacting protein kinase family members. Biochim. Biophys. Acta Mol Cell Res.1866, 1676-1686.
  • Saul, V.V., Seibert, M., Krüger, M., Jeratsch, S. Kracht, M. and M.L. Schmitz (2019) ULK1/2 restrict the formation of inducible SINT-speckles, a new class of membrane-less organelles controlling the threshold of TBK1 activation. iSCIENCE 19, 527-544.
  • Wiwie C, Kuznetsova I, Mostafa A, Rauch A, Haakonsson A, Barrio-Hernandez I, Blagoev B, Mandrup S, Schmidt HHHW, Pleschka S, Röttger R, Baumbach J. Time-Resolved Systems Medicine Reveals Viral Infection-Modulating Host Targets. Syst Med (New Rochelle). 2019 Mar 28;2(1):1-9. doi: 10.1089/sysm.2018.0013. eCollection 2019.
  • Mostafa A, Abdelwhab EM, Mettenleiter TC, Pleschka S. Zoonotic Potential of Influenza A Viruses: A Comprehensive Overview. Viruses. 2018 Sep 13;10(9). pii: E497. doi: 10.3390/v10090497. Review.
  • Dam S, Kracht M, Pleschka SSchmitz ML. The Influenza A Virus Genotype Determines the Antiviral Function of NF-κN. J Virol. 2016 Aug 12;90(17):7980-90. doi: 10.1128/JVI.00946-16. Print 2016 Sep 1.
  • Kanrai P, Mostafa A, Madhugiri R, Lechner M, Wilk E, Schughart K, Ylösmäki L, Saksela K, Ziebuhr J, Pleschka S. Identification of specific residues in avian influenza A virus NS1 that enhance viral replication and pathogenicity in mammalian systems. J Gen Virol. 2016 Sep;97(9):2135-2148. doi: 10.1099/jgv.0.000542. Epub 2016 Jul 12.
  • Schmier S, Mostafa A, Haarmann T, Bannert N, Ziebuhr J, Veljkovic V, Dietrich U, Pleschka S. In Silico Prediction and Experimental Confirmation of HA Residues Conferring Enhanced Human Receptor Specificity of H5N1 Influenza A Viruses. Sci Rep. 2015; 5: 11434. Published online 2015 Jun 19. doi: 10.1038/srep11434
Principal investigator:

Prof. Dr. Michael Kracht

Rudolf-Buchheim-Institut für Pharmakologie
Justus-Liebig-Universität Gießen
Schubertstraße 81
35392 Gießen

Phone: 0641-99 47600
E-Mail: michael.kracht(at)pharma.med.uni-giessen(dot)de

Research areas: Signal Transduction, Molecular Virology

Based on their cell biological experience, the Kracht group has made a major and systematic effort to determine the entire transcriptomes, proteomes and phospho-, acetyl-, and ubiquityl proteomes of human coronavirus (HCoV) 229E-infected cells at high resolution. These data sets revealed hundreds of new HCoV-229E-regulated cellular genes and proteins and also demonstrated that the HCoV-229E M- and N-proteins are heavily phosphorylated and acetylated. Furthermore, the Kracht group determined the chromatin landscape of HCoV-229E-infected cells and found more than 1000 CoV-regulated enhancers. This comprehensive insight into transcriptional and post-transcriptional mechanisms in response to coronavirus infection offers multiple avenues for further investigation of virus-host interactions at the molecular level.

Project-related publications of the investigator:
  • Weber A, Dam S, Saul VV, Kuznetsova I, Muller C, Fritz-Wolf K, Becker K, Linne U, Gu H, Stokes MP, Pleschka S, Kracht M, Schmitz ML. 2019. Phosphoproteome Analysis of Cells Infected with Adapted and Nonadapted Influenza A Virus Reveals Novel Pro- and Antiviral Signaling Networks. J Virol 93(13). pii: e00528-19. doi: 10.1128.
  • Weiterer SS, Meier-Soelch J, Georgomanolis T, Mizi A, Beyerlein A, Weiser H, Brant L, Mayr-Buro C, Jurida L, Beuerlein K, Muller H, Weber A, Tenekeci U, Dittrich-Breiholz O, Bartkuhn M, Nist A, Stiewe T, van IWF, Riedlinger T, Schmitz ML, Papantonis A, Kracht M. 2019. Distinct IL-1alpha-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner. EMBO J 39(1):e101533. doi.
  • Saul VV, Seibert M, Kruger M, Jeratsch S, Kracht M, Schmitz ML. 2019. ULK1/2 Restricts the Formation of Inducible SINT-Speckles, Membraneless Organelles Controlling the Threshold of TBK1 Activation. iScience 19:527-544. doi: 10.1016.
  • Meier-Soelch J, Jurida L, Weber A, Newel D, Kim J, Braun T, Schmitz ML, Kracht M. 2018. RNAi-Based Identification of Gene-Specific Nuclear Cofactor Networks Regulating Interleukin-1 Target Genes. Frontiers in Immunology 9:775. doi: 10.3389.
  • Schmitz ML, Shaban MS, Albert BV, Gokcen A, Kracht M. 2018. The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-kappaB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection. Biomedicines 6(2). pii: E58. doi: 10.3390.
  • Poppe M, Wittig S, Jurida L, Bartkuhn M, Wilhelm J, Muller H, Beuerlein K, Karl N, Bhuju S, Ziebuhr J, Schmitz ML, Kracht M. 2017. The NF-kappaB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells. PLoS Pathog 3(3):e1006286. doi: 10.1371.
Principal investigator:

Prof. Dr. Harald Renz

Institut für Laboratoriumsmedizin
Philipps-Universität Marburg
35043 Marburg

Phone: 06421-58 66235

Principal investigator:

PD Dr. Chrysanthi Skevaki

Institut für Laboratoriumsmedizin
Philipps-Universität Marburg
35043 Marburg

Phone: 06421-58 63850
E-Mail: chrysanthi.skevaki(at)uk-gm(dot)de

Research areas: Molecular Virology, Immunology, Allergy

Respiratory RNA viruses play an important role in the initiation and exacerbation of chronic inflammatory lung disease, including allergic asthma. Clinically relevant pathogens include influenza virus (IAV), rhinovirus (RV), and respiratory syncytial virus (RSV). In the first funding period, the Renz and Skevaki groups focused on the role of IAV infections in the development of allergic asthma, utilizing a well-established murine animal model of experimental asthma. Surprisingly, they found that a single preceding H1N1 IAV infection rendered the mice resistant to subsequent development of allergic airway inflammation, airway hyperresponsiveness and Th2-immune responses. This protection was dependent on the presence of both CD4+ and CD8+ T effector memory cells. By means of comprehensive in silico analyses, ex vivo T-cell peptide stimulation, and in vivo immunization experiments, two MHC-class I H1N1 peptides and two MHC-class II H1N1 peptides, which cross-react with three ovalbumin-derived peptides, were identified. These data illustrate for the first time heterologous immunity of virus-infected animals towards an allergen.

Project-related publications of the investigators:
  • Taka S, Nikopoulou C, Polyzos A, Megremis S, Skevaki CL, Roumpedaki E, Trochoutsou A, Thanos D, Papadopoulos NG. Effects of cryopreservation on antiviral responses of primary airway epithelial cells. Allergy. 2019 Dec 27.
  • Matricardi PM, Dramburg S, Potapova E, Skevaki CRenz H. Molecular diagnosis for allergen immunotherapy. J Allergy Clin Immunol. 2019 Mar;143(3):831-843.
  • Skevaki CRenz H. Advances in mechanisms of allergic disease 2017. J Allergy Clin Immunol. 2018 Oct 10. pii: S0091-6749(18)31436-2.
  • Potaczek DP, Unger SD, Zhang N, Taka S, Michel S, Akdağ N, Lan F, Helfer M, Hudemann C, Eickmann M, Skevaki C, Megremis S, Sadewasser A, Alashkar Alhamwe B, Alhamdan F, Akdis M, Edwards MR, Johnston SL, Akdis CA, Becker S, Bachert C, Papadopoulos NG, Garn H, Renz H. Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses. J Allergy Clin Immunol. 2018 Aug 14. pii: S0091-6749(18)31139-4.
  • Pusch E, Renz HSkevaki C. Respiratory virus-induced heterologous immunity. Allergo J Int. 2018 Mar 26.
  • Skevaki C, Hudemann C, Matrosovich M, Möbs C, Paul S, Wachtendorf A, Alashkar Alhamwe B, Potaczek DP, Hagner S, Gemsa D, Garn H, Sette A, Renz H. Influenza-derived peptides cross-react with allergens and provide asthma protection. J Allergy Clin Immunol. 2018 Sep;142(3):804-814.
  • Schwarze J, Openshaw P, Jha A, Del Giacco SR, Firinu D, Tsilochristou O, Roberts G, Selby A, Akdis C, Agache I, Custovic A, Heffler E, Pinna G, Khaitov M, Nikonova A, Papadopoulos N, Akhlaq A, Nurmatov U, Renz H, Sheikh A, Skevaki C. Influenza burden, prevention and treatment in asthma - a scoping review by the EAACI influenza in asthma task force. Allergy. 2017 Nov 6.
  • Nilsson L, Brockow K, Alm J, Cardona V, Caubet JC, Gomes E, Jenmalm MC, Lau S, Netterlid E, Schwarze J, Sheikh A, Storsaeter J, Skevaki C, Terreehorst I, Zanoni G. Vaccination and allergy: EAACI position paper, practical aspects. Pediatr Allergy Immunol. 2017 Nov;28(7):628-640.
Principal investigator:

Prof. Dr. med. Susanne Herold

Med. Klinik II, Infektiologie
Justus-Liebig-Universität Gießen
Klinikstraße 36
35392 Giessen

Phone: 0641-98 542552
E-Mail: Susanne.Herold(at)innere.med.uni-giessen(dot)de

Research areas: Pneumology, Infectious Diseases, Cell Biology, Molecular Virology

Influenza A virus (IAV) pneumonia is characterized by severe airway and alveolar injury, followed by stem cell-mediated epithelial repair. This project aims at (i) understanding which host signalling pathways at the virus-host interface drive alveolar epithelial cell repair from distinct lung stem cell niches and (ii) elucidating how viral pathogenicity factors impact these mechanisms, resulting in aggravated damage of the distal lung epithelium and in impaired or aberrant repair after IAV-induced pneumonia. In the previous funding period, the Herold group characterized mechanisms that result in impaired alveolar epithelial barrier function after IAV infection in vivo. Particularly, a newly defined pool of local lung epithelial stem/progenitor cells (EpiSPC) was found to be essential for bronchoalveolar tissue regeneration after IAV-induced injury. Their regenerative response depended on cooperation with mesenchymal cells of the stem cell niche and involved a β-catenin/FGF10/FGFR2b signalling axis as well as epithelial GM-CSF. Furthermore, it was demonstrated that IAV infection of the stem cell niche critically impacts the capacity of EpiSPC to mediate coordinated tissue repair. The distinct role and regulation of GM-CSF in EpiSPC-mediated repair as well as the detailed consequences of IAV infection of the stem cell niche with respect to restitutio ad integrum of the injured lung tissue will be elucidated in the 2nd funding period.

Project-related publications of the investigator:
  • Salwig I, Spitznagel B, Vazquez-Armendariz AI, Khaloogi K, Herold S, Szibor M, Braun T. Bronchioalveolar stem cells are a dominant source for regeneration of distal lung epithelia. EMBO J, 38(12), pii: e102099, 2019.
  • Schmoldt C, Vazquez-Armendariz AI, Shalashova I, Selvakumar B, Bremer CM, Peteranderl C, Witte B, Gattenloehner S, Fink L, Morty RE, Pleschka S, Seeger W. Guenther A, Herold S. IRE-1 signalling as putative therapeutic target for influenza virus-induced pneumonia. Am J Respir Cell Mol Biol 61(4):537-40, 2019
  • El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Kosanovic D, Schwind F, Schermuly RT, Henneke I, MacKenzie B, Quantius J, Herold S, Ntokou A, Ahlbrecht K, Morty RE, Günther A, Seeger W and Bellusci S. Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis. Cell Stem Cell 20(2):261-273, 2017
  • Quantius J, Schmoldt C, Becker C, El Agha E, Wilhelm J, Morty RE, Vadasz I, Mayer K, Gattenloehner S, Fink L, Matrosovich M, Seeger W, Lohmeyer J, Bellusci S, Herold S. Influenza virus infects epithelial stem/progenitor cells of the distal lung: impact on Fgfr2b-driven epithelial repair. PLoS Pathog 12(6):e1005544, 2016
  • Peteranderl C, Morales-Nebreda L, Selvakumar B, Lecuona E, Vadász I, Morty RE, Schmoldt C, Bespalowa J, Wolff T, Pleschka S, Mayer K, Gattenloehner S, Fink L, Lohmeyer J, Seeger W, Sznajder JI, Mutlu G, Budinger GRS, Herold S. Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. J Clin Invest 126(4):1566-80, 2016
  • Herold S, Hoegner K, Vadász I, Gessler T, Wilhelm J, Mayer K, Morty RE, Walmrath HD, Seeger W, Lohmeyer J. Inhaled GM-CSF as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med. 189(5):609-11, 2014
  • Unkel B, Hoegner K, Clausen BE, Lewe-Schlosser P, Bodner J, Gattenloehner S, Seeger W, Lohmeyer J, Herold S. Alveolar epithelial cells orchestrate dendritic cell functions by release of granulocyte-macophage colony stimulating factor in influenza virus pneumonia. J Clin Invest 122:3652-64, 2012
  • Herold S, Shafiei Tabar T, Janßen H, Högner, K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmüller M, Lohmeyer J. Exudate macrophages attenuate epithelial injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183:1380-90, 2011
  • Cakarova L, Marsh L, Wilhelm J, Mayer K, Grimminger F, Seeger W, Lohmeyer J, Herold S. Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte macrophage- colony stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med 180:521-32, 2009
  • Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Seeger W, Lohmeyer J. Lung epithelial apoptosis in influenza virus pneumonia: The role of macrophage TNF-related apoptosis-inducing ligand. J Exp Med 205(13):3065-77, 2008