How can we stop the life cycle of these pathogens at an early step?

What is this research project about?

What is this research project about?

Persistent viral infections with human herpesviruses represent a serious threat to susceptible and immunocompromised individuals like newborn babies, senior individuals, transplant recipients and persons with other immune defects or concurrent infections. The β-herpesvirus HCMV (Human Cytomegalovirus) for example infects nearly every second person of an industrialised country. While a lot of people do not notice such an infection at all due to mild symptoms, an infection of an unborn baby by HCMV can lead to life threatening consequences and birth defects of the newborn. Other herpesviruses such as the γ-herpesvirus KSHV (Kaposi Sarcoma Herpesvirus) are known to trigger cancer in humans. KSHV has been classified as class I carcinogen by WHO (World Health Organization) and causes approximately 1% of all cancer cases worldwide.

What’s the current status?

Today, antiviral drugs against herpesviruses exist. These drugs are inhibiting the replication of the viral genome and thus stop virus reproduction. Unfortunately, a lot of the antiviral inhibitors are not effective enough to suppress viral replication fully and permanently and they cannot eliminate the infection. With one exception, all currently available antiviral drugs attack the herpesviruses at the step of viral DNA synthesis by blocking the viral DNA polymerase, the synthesis machinery of viral DNA, which is needed during viral replication. Inhibiting the virus at this stage still allows the expression of certain viral genes and proteins that may play a role during viral pathogenesis.

What are the project goals?

Being able to target other steps in the viral life cycle would significantly improve our ability to devise more efficacious forms of antiviral combination therapy for the affected patients. In particular, it would be desirable to target the immediate-early or early stages of the herpesviral life cycle, as viral genes and proteins expressed during the early stages contribute to the viral pathogenic properties and are required for the ability of these viruses to persist longterm in an infected individual. The key intellectual challenge is to pinpoint points in the viral life cycle and in the complex interaction network of viral and cellular proteins that could be amenable to therapeutic intervention.

How do we get there?

From our 20 year long experience of working on the γ-herpesvirus KSHV, we learned a lot about how the virus manages to establish such a long-lasting infection, to escape the detection by the immune system of the host and yet to be transferred from mother to daughter cell during cell division. In doing so, we concentrated on a particular viral protein, the latency-associated nuclear antigen LANA, which mediates many of these functions and can also reprogram the infected cell for the benefit of the virus (e.g. Rainbow et al., 1997, Platt et al., 1999; Ottinger et al., 2006, 2009; Viejo-Borbolla et al., 2003, 2005; Jäger et al., 2012; Zhang et al., 2016; Mariggio et al., 2017). An important aspect of our work is to understand the structure of LANA (Hellert et a., 2013, 2015) and the nature of tiny ‘territories’ in the nucleus of the infected cell in which the virus resides in a latent form. Over the last 20 years we have also characterized the function of a viral non-structural membrane protein, pK15, which is necessary during the early stages of productive early replication and initiates intracellular signaling pathways required for viral replication. For both LANA and pK15 we have, in collaboration with another RESIST scientist, M. Empting, developed first generation small molecule inhibitors that antagonize the function of LANA or pK15-dependent signal transduction. Within RESIST we want to transfer our gained knowledge and experience from the work on KSHV LANA to other herpesviruses, such as the β-herpesvirus HCMV. We seek to find ‘weak spots’ in the interaction between the virus and the infected cell and to target these spots with novel and more efficient antiviral drugs.

Projectleaders

Project title: Comparative Approach to β and γ-herpesvirus Persistence

Prof. Dr. Thomas F. Schulz

Projekte: D1, D3

  Leiter
  Institut für Virologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-4107
  +49 511 532-8736
 
  Schulz.Thomas
@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Thomas Krey

Projekte: B10, D1, D3

 
  Institut für Biochemie, Universität Lübeck
  Ratzeburger Allee 160
23562 Lübeck
  +49-451-3101-3102
  +49-451-3101-3104
 
  krey@biochem.uni-luebeck.de
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Prof. Dr. Martin Messerle

Projekte: D1, D2

 
  Cytomegalovirus (CMV) research group, Institut für Virologie
Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-4320
  +49 511 532-8736
 
  Messerle.Martin
@mh-hannover.de
  DOWNLOAD CV

Prof. Dr. Kay Grünewald

Projekte: D1, D2

 
  Centre for Structural Systems Biology (CSSB)
  c/o Deutsches Elektronen-Synchrotron DESY
Notkestraße 85, Building 15
2607 Hamburg
  +49 40 8998-87700
 
 
  kay.gruenewald
@cssb-hamburg.de
  DOWNLOAD CV

Project D1 Publications

You will find project related publications here.

  1. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, Scheible R, Rusch S, Gasteiger LM, Grimbacher B, Mahlaoui N, Ehl S; ESID Registry Working Party and collaborators. J Allergy Clin Immunol Pract. 2019 Jul – Aug;7(6):1763-1770. doi: 10.1016/j.jaip.2019.02.004. Epub 2019 Feb 15.
  2. Evaluating laboratory criteria for combined immunodeficiency in adult patients diagnosed with common variable immunodeficiency. von Spee-Mayer C, Koemm V, Wehr C, Goldacker S, Kindle G, Bulashevska A, Proietti M, Grimbacher B, Ehl S, Warnatz K. Clin Immunol. 2019 Jun;203:59-62. doi: 10.1016/j.clim.2019.04.001. Epub 2019 Apr 17.
  3. Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency. Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, Schubert D, Warnatz K, Grimbacher B. Front Immunol. 2019 Apr 16;10:568. doi: 10.3389/fimmu.2019.00568. eCollection 2019. Erratum in: Front Immunol. 2019 Jun 28;10:1490.
  4. Corrigendum: Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency. Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, Schubert D, Warnatz K, Grimbacher B. Front Immunol. 2019 Jun 28;10:1490. doi: 10.3389/fimmu.2019.01490. eCollection 2019.
  5. The German National Registry of Primary Immunodeficiencies (2012-2017). El-Helou SM, Biegner AK, Bode S, Ehl SR, Heeg M, Maccari ME, Ritterbusch H, Speckmann C, Rusch S, Scheible R, Warnatz K, Atschekzei F, Beider R, Ernst D, Gerschmann S, Jablonka A, Mielke G, Schmidt RE, Schürmann G, Sogkas G, Baumann UH, Klemann C, Viemann D, von Bernuth H, Krüger R, Hanitsch LG, Scheibenbogen CM, Wittke K, Albert MH, Eichinger A, Hauck F, Klein C, Rack-Hoch A, Sollinger FM, Avila A, Borte M, Borte S, Fasshauer M, Hauenherm A, Kellner N, Müller AH, Ülzen A, Bader P, Bakhtiar S, Lee JY, Heß U, Schubert R, Wölke S, Zielen S, Ghosh S, Laws HJ, Neubert J, Oommen PT, Hönig M, Schulz A, Steinmann S, Schwarz K, Dückers G, Lamers B, Langemeyer V, Niehues T, Shai S, Graf D, Müglich C, Schmalzing MT, Schwaneck EC, Tony HP, Dirks J, Haase G, Liese JG, Morbach H, Foell D, Hellige A, Wittkowski H, Masjosthusmann K, Mohr M, Geberzahn L, Hedrich CM, Müller C, Rösen-Wolff A, Roesler J, Zimmermann A, Behrends U, Rieber N, Schauer U, Handgretinger R, Holzer U, Henes J, Kanz L, Boesecke C, Rockstroh JK, Schwarze-Zander C, Wasmuth JC, Dilloo D, Hülsmann B, Schönberger S, Schreiber S, Zeuner R, Ankermann T, von Bismarck P, Huppertz HI, Kaiser-Labusch P, Greil J, Jakoby D, Kulozik AE, Metzler M, Naumann-Bartsch N, Sobik B, Graf N, Heine S, Kobbe R, Lehmberg K, Müller I, Herrmann F, Horneff G, Klein A, Peitz J, Schmidt N, Bielack S, Groß-Wieltsch U, Classen CF, Klasen J, Deutz P, Kamitz D, Lassay L, Tenbrock K, Wagner N, Bernbeck B, Brummel B, Lara-Villacanas E, Münstermann E, Schneider DT, Tietsch N, Westkemper M, Weiß M, Kramm C, Kühnle I, Kullmann S, Girschick H, Specker C, Vinnemeier-Laubenthal E, Haenicke H, Schulz C, Schweigerer L, Müller TG, Stiefel M, Belohradsky BH, Soetedjo V, Kindle G, Grimbacher B. Front Immunol. 2019 Jul 19;10:1272. doi: 10.3389/fimmu.2019.01272. eCollection 2019.
  6. The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies. Jandus P, Boligan KF, Smith DF, de Graauw E, Grimbacher B, Jandus C, Abdelhafez MM, Despont A, Bovin N, Simon D, Rieben R, Simon HU, Cummings RD, von Gunten S. Blood. 2019 Nov 28;134(22):1941-1950. doi: 10.1182/blood.2019001705.
  7. Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity. Jägle S, Heeg M, Grün S, Rensing-Ehl A, Maccari ME, Klemann C, Jones N, Lehmberg K, Bettoni C, Warnatz K, Grimbacher B, Biebl A, Schauer U, Hague R, Neth O, Mauracher A, Pachlopnik Schmid J, Fabre A, Kostyuchenko L, Führer M, Lorenz MR, Schwarz K, Rohr J, Ehl S. Clin Immunol. 2019 Nov 23;210:108316. doi: 10.1016/j.clim.2019.108316.
  8. Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1. Schröder C, Sogkas G, Fliegauf M, Dörk T, Liu D, Hanitsch LG, Steiner S, Scheibenbogen C, Jacobs R, Grimbacher B, Schmidt RE, Atschekzei F. Front Immunol. 2019 Nov 14;10:2618. doi: 10.3389/fimmu.2019.02618. eCollection 2019.
  9. Structural Noninfectious Manifestations of the Central Nervous System in Common Variable Immunodeficiency Disorders. van de Ven A, Mader I, Wolff D, Goldacker S, Fuhrer H, Rauer S, Grimbacher B, Warnatz K. J Allergy Clin Immunol Pract. 2019 Dec 16. pii: S2213-2198(19)31026-8. doi: 10.1016/j.jaip.2019.11.039.
  10. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Pérez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarström L, Dogu F, Haskologlu S, İkincioğulları AI, Bal SK, Baris S, Kilic SS, Karaca NE, Kutukculer N, Girschick H, Kolios A, Keles S, Uygun V, Stepensky P, Worth A, van Montfrans JM, Peters AM4, Meyts I, Adeli M, Marzollo A, Padem N, Khojah AM, Chavoshzadeh Z, Stefanija MA, Bakhtiar S, Florkin B, Meeths M, Gamez L, Grimbacher B, Seppänen MR, Lankester A, Gennery AR, Seidel MG; Inborn Errors, Clinical, and Registry Working Parties of the European Society for Blood and Marrow Transplantation (EBMT) and the European Society of Immunodeficiencies (ESID). J Allergy Clin Immunol. 2019 Dec 27. pii: S0091-6749(19)32603-X. doi: 10.1016/j.jaci.2019.12.896.

Project D1
Publications