Gunther Hartmann

Gunther Hartmann, November 2009

Gunther Hartmann (born 7 December 1966 in Leutkirch) is a German clinical pharmacologist and immunologist. Since 2007 he has been the Professor of Clinical Chemistry and Clinical Pharmacology at the University Hospital of the University of Bonn.

Life

In 1986, Hartmann obtained his school leaving certificate (Abitur) from the Salvator College Catholic High School in Bad Wurzach. In 1986, he began his studies of Medicine at the University of Ulm, and received his Ph.D. from the institution's Department of Clinical Genetics in 1994. From 1995 to 1997 he was a research assistant at the city Medical Clinic at the Ludwig Maximilian University of Munich. From 1998 to 1999, he worked with Arthur Krieg as a postdoctoral fellow at the Department of Internal Medicine at the University of Iowa in the United States.

In 2001 he obtained his habilitation in Clinical Pharmacology. In 2005 he was made head of the Department of Clinical Pharmacology, and in 2007 he was appointed Professor of Clinical Chemistry and Clinical Pharmacology at the Central Laboratory at the University of Bonn. Since 2009 he has been a member of the Expert Committee on Cancer Therapy Trials at the German Cancer Aid organization. Since 2010 he has been the spokesman of the ImmunoSensation Cluster of Excellence,[1] which has been funded by the Deutsche Forschungsgemeinschaft (DFG) since November 2012. From 2011 to 2012, he was president of the international Oligonucleotide Therapeutic Society.[2]

Scientific interests

The immune system senses pathogens and damage and subsequently initiates a response that effectively protects the organism from harm. Specific receptor systems evolved to detect distress early on and to initiate the appropriate responses. Different classes of receptors sense various molecular entities. While the immune system employs individually created receptors (recombination of genetic elements) to detect foreign proteins (adaptive immune system, e.g. T cell and B cell receptors and antibodies), the innate arm of the immune system applies germline-encoded receptors to detect microbial or damaged molecules including nucleic acid (DNA and RNA). Innate immune sensing of nucleic acids is essential for immune recognition of viruses and has been the scientific focus of the Hartmann group for more than 17 years. His scientific achievements have been awarded with the Gottfried Wilhelm Leibniz Prize (information and video:[3]). Besides immune recognition of viruses, immune sensing of nucleic acids is involved in bacterial infection, in tumor biology and autoimmune disease.

Hartmann´s group contributed to the understanding of several innate immune receptors. 1996 in the laboratory of Prof. Stefan Endres in Munich he made the unexpected observation that single-stranded DNA oligonucleotides with certain chemical modifications activate human immune cells.[4][5] During his DFG-funded fellowship in the laboratory of Prof. Arthur Krieg in Iowa City (USA) in 1998/1999 he identified the molecular patterns that are responsible for immunorecognition of DNA (so-called CpG motifs detected via the innate immune receptor Toll-like receptor 9, TLR9).[6][7][8][9] Back in Munich he continued to work on the immunological activities of CpG oligonucleotides in the human system.[10][11] He found that the direct recognition of CpG motifs via TLR9 is restricted to B cells and plasmacytoid dendritic cells, the only two immune cell subsets in humans that express TLR9. Notably, CpG DNA was the first molecularly defined stimulus to activate the plasmacytoid dendritic cell, a cell type first described only in 1999.[12] Based on the insight in the biological function he established different classes of CpG oligonucleotides (CpG-A, CpG-B and CpG-C).[13] Together with Arthur Krieg he published the CpG oligonucleotide ODN 2006 which later was clinically developed by Coley Pharmaceuticals and is currently (2013) studied in phase III clinical trials as immune adjuvant in a novel type of cancer vaccine.[14]

In 2002 he turned to innate immune sensing of RNA. In 2005 his group reported that siRNA (short interfering RNA) sequence dependently stimulates Toll-like receptor 7 (TLR7). These findings gained great impact in the field siRNA. Furthermore, the identification of RNA motifs recognized by TLR7 allowed the development of new types of immunostimulatory oligonucleotides with novel immunological profiles.[15] The combination of immunostimulation with the technology of siRNA (gene silencing) opened new opportunities for oligonucleotide therapeutics.[16]

The next scientific focus was on immune sensing of RNA in the cytosol of cells. It turned out that this sensing pathway is related to RNA interference (siRNA, microRNA). In RNA interference, the helicase DICER cleaves longer double-stranded RNA molecules into shorter siRNA or microRNA which are then integrated into the RISC complex. The antisense strand within this RISC complex is responsible for the sequence specificity of silencing of the corresponding target mRNA. In more primitive organisms such as worms RNA interference is used to destroy foreign nucleic acids. This defense mechanism can be regarded as a specific form of a nucleic acid-based immune system in which the newly generated siRNAs function as immune effector molecules. In higher organisms such as vertebrates, this DICER-based defense system is replaced by another defense mechanism. Two helicases related to DICER, RIG-I and MDA5, take over the challenge to detect foreign RNA in the cytosol of cells. However, unlike the helicase DICER, upon recognition of foreign RNA RIG-I and MDA5 trigger a broad spectrum of antiviral activities in the cell including type I IFN. Hartmann and colleagues identified the specific RNA ligand structure detected by RIG-I: RNA with a blunt end and a 5´-triphosphate[17][18]. In a subsequent publication, his group elucidated how the molecular structure of the binding pocket of RIG-I precludes binding of N1-2′O methylated RNA, thus preventing recognition of endogenous mRNA by the innate immune system.[19]

Another focus is the immune sensing of DNA. Here, the Hartmann group contributed to the identification and molecular characterization of the cGAS - STING pathway. In this pathway, the binding of double-stranded DNA to the enzyme cGAS leads to the formation of a novel previously unknown second messenger molecule (G (2 ', 5'), pA (3 ', 5') p). The identification of this molecule uncovered a new principle in innate immunity: the formation of a second messenger molecule which triggers the induction of a broad antiviral signaling cascade via another receptor (STING). Subsequent work by the group revealed that this pathway is also involved in the pathogenesis of autoimmune diseases such as lupus erythematosus. Under UV exposure, oxidative chemical damage to endogenous DNA inhibits its cytosolic degradation the DNase TREX1, whichs leads to accumulation of DNA in the cytosol and activation of the cGAS / STING pathway.[20]

The scientific topic of the Hartmann group is integral part of the new excellence cluster ImmunoSensation funded by the DFG and led by Hartmann as speaker.[21] The application of nucleic acid sensing for the treatment of infection is studied in the context of the Bonn-Cologne site of the German Centre for Infection Research of the Helmholtz association (DZIF:[22]). Furthermore, the Hartmann is actively pursuing the translation of the novel findings into new therapies. The BMBF-funded GoBio project "RNA therapeutics[23] develops a RIG-I ligand for the treatment of melanoma. Clinical trials will be performed by a BMBF co-sponsored spin-off company (ImmunOligo GmbH). In 2013 this project was awarded in the competition Science4Life.[24]

Honours

References

  1. ↑ "Speaker". ImmunoSensation Cluster of Excellence. Retrieved 19 July 2013.
  2. ↑ "Gunther Hartmann M.D.: Executive Profile & Biography - Bloomberg". www.bloomberg.com.
  3. ↑ http://www.dfg.de/gefoerderte_projekte/wissenschaftliche_preise/leibniz-preis/2012/hartmann_kurts/
  4. ↑ Hartmann G, Krug A, Eigler A, Moeller J, Murphy J, Albrecht R, Endres S. Specific suppression of human tumor necrosis factor-a synthesis by antisense oligodeoxynucleotides. Antisense Nucleic Acid Drug Dev 1996; 6: 291-99
  5. ↑ Hartmann G, Krug A, Waller-Fontaine K, Endres S. Oligodeoxynucleotides enhance lipopolysaccharide-stimulated synthesis of tumor necrosis factor: dependence on phosphorothioate modification and reversal by heparin. Mol Med 1996; 2: 429-438
  6. ↑ Hartmann G, Krieg AM. CpG DNA and LPS induce distinct patterns of activation in human monocytes. Gene Ther 1999; 6: 893
  7. ↑ Hartmann G, Weiner G, Krieg AM. CpG DNA as a signal for growth, activation and maturation of human dendritic cells PNAS 1999; 96: 9305
  8. ↑ Hartmann G, Krieg A. M. Mechanism and function of a newly identified CpG DNA motif in human primary cells. J Immunol 2000; 164: 944
  9. ↑ Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, Rasmussen WL, Waldschmidt M, Sajuthi D, Purcell RH, Davis H, Krieg AM. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol 2000; 164: 1617
  10. ↑ Rothenfusser S, Hornung V, Krug A, Towarowski A, Krieg AM, Endres S, Hartmann G. Distinct CpG oligonucleotide sequences activate human γδ T cells via interferon-alpha/beta. Eur J Immunol 2001; 31: 3525-3534
  11. ↑ Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdoerfer B, Giese T, Endres S, Hartmann G. Quantitative expression of TLR1-10 mRNA in cellular subsets of human PBMC and sensitivity to CpG ODN. J Immunol 2002; 168: 4531-37
  12. ↑ Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R, Giese T, Engelmann H, Endres S, Krieg AM, Hartmann G. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40L to induce high amounts of IL-12. Eur J Immunol 2001, 31: 3026-37
  13. ↑ Krug A, Rothenfusser S, Hornung V, Jahrsdörfer B, Ballas Z, Endres S, Krieg AM, Hartmann G. Identification of CpG oligonucleotide sequences with high induction of IFN-a/-b in plasmacytoid dendritic cells. Eur J Immunol 2001; 31: 2154-63
  14. ↑ http://www.meb.uni-bonn.de/klinpharm/index.php?page=ag-hartmann-schlee
  15. ↑ Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, Endres S, Hartmann G. Sequence-specific potent induction of IFN-a by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 2005; 11: 263-70
  16. ↑ http://www.dfg.de/download/pdf/gefoerderte_projekte/preistraeger/gwl-preis/2012/laudatio_hartmann.pdf
  17. ↑ Hornung, V.; Ellegast, J.; Kim, S.; Brzozka, K.; Jung, A.; Kato, H.; Poeck, H.; Akira, S.; Conzelmann, K.-K.; Schlee, M.; Endres, S.; Hartmann, G. (10 November 2006). "5'-Triphosphate RNA Is the Ligand for RIG-I". Science. 314 (5801): 994–997. doi:10.1126/science.1132505.
  18. ↑ Schlee, Martin; Roth, Andreas; Hornung, Veit; Hagmann, Cristina Amparo; Wimmenauer, Vera; Barchet, Winfried; Coch, Christoph; Janke, Markus; Mihailovic, Aleksandra; Wardle, Greg; Juranek, Stefan; Kato, Hiroki; Kawai, Taro; Poeck, Hendrik; Fitzgerald, Katherine A.; Takeuchi, Osamu; Akira, Shizuo; Tuschl, Thomas; Latz, Eicke; Ludwig, Janos; Hartmann, Gunther (July 2009). "Recognition of 5′ Triphosphate by RIG-I Helicase Requires Short Blunt Double-Stranded RNA as Contained in Panhandle of Negative-Strand Virus". Immunity. 31 (1): 25-34. doi:10.1016/j.immuni.2009.05.008. PMID 19576794.
  19. ↑ Schuberth-Wagner, Christine; Ludwig, Janos; Bruder, Ann Kristin; Herzner, Anna-Maria; Zillinger, Thomas; Goldeck, Marion; Schmidt, Tobias; Schmid-Burgk, Jonathan L.; Kerber, Romy; Wolter, Steven; Stümpel, Jan-Philip; Roth, Andreas; Bartok, Eva; Drosten, Christian; Coch, Christoph; Hornung, Veit; Barchet, Winfried; Kümmerer, Beate M.; Hartmann, Gunther; Schlee, Martin (July 2015). "A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N1-2′O-Methylated Self RNA". Immunity. 43 (1): 41–51. doi:10.1016/j.immuni.2015.06.015. PMID 26187414.
  20. ↑ Gehrke, Nadine; Mertens, Christina; Zillinger, Thomas; Wenzel, Jörg; Bald, Tobias; Zahn, Sabine; Tüting, Thomas; Hartmann, Gunther; Barchet, Winfried (September 2013). "Oxidative Damage of DNA Confers Resistance to Cytosolic Nuclease TREX1 Degradation and Potentiates STING-Dependent Immune Sensing". Immunity. 39 (3): 482–495. doi:10.1016/j.immuni.2013.08.004. PMID 23993650.
  21. ↑ http://immunosensation.de/about-us/governance/speaker.html
  22. ↑ http://www.dzif.de/</
  23. ↑ "Archived copy". Archived from the original on 2013-10-29. Retrieved 2013-09-23.
  24. ↑ http://www.science4life.de/Preistraeger/Runde2013.aspx
  25. ↑ BMBF-Wettbewerb BioFuture: Alle Preisträger (PDF; 87 kB)
  26. ↑ wilhelmvaillantstiftung.de: Informationen zum Wilhelm Vaillant-Preis Archived 2014-02-27 at the Wayback Machine. (in German)
  27. ↑ "Prizewinners: Gottfried Wilhelm Leibniz Programme: 2012: Prof. Dr. Gunther Hartmann & Prof. Dr. Christian Kurts". Deutsche Forschungsgemeinschaft. Retrieved 18 July 2013.
  28. ↑ "List of Members". German Academy of Sciences Leopoldina. Retrieved 11 September 2013.
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