Which new therapeutic options arise when the process of herpesviral assembly is explored?

What is this research project about?

HSV1 (red) in nerve cells (tubulin in blue)

What is this research project about?

While a healthy immune system is able to control herpesviruses, primary and recurrent infections can cause severe disease; particularly very early in life and in the elderly as well as in individuals with increased susceptibility, either due to genetic factors or to immune suppression, e.g., after organ transplantation or for those living with HIV/AIDS. Due to their ubiquitous prevalence, the disease burden of herpesviruses is high in industrialized and developing countries. Diseases range from stigmatizing skin lesions to unbearable pain, life-threatening encephalitis and cancers. The human herpesviruses responsible for the most serious and even life-threatening complications are human cytomegalovirus (HCMV), Herpes Simplex virus (HSV-1 and HSV-2), Varicella Zoster Virus (VZV), and Kaposi Sarcoma Herpesvirus (KSHV).

What’s the current status?

Only few licensed drugs are in clinical use to treat herpesvirus infections, and these target mainly enzymes required for viral DNA replication. Furthermore, these drugs have severe side effects, and resistant viral strains emerge upon prolonged treatment. The recently approved Letermovir that inhibits the HCMV terminase, may represent the first drug to expand our scope of antiviral targets. However, first resistant HCMV mutants have already been described indicating that combination therapies – as used successfully against HIV and HCV – are required. To this end, our research aims at the identification and characterization of unique protein-protein interactions that are essential for virion assembly and therefore potentially represent novel druggable targets. This strategy will pave the way for advanced combination therapies with reduced side effects, and a much lower risk of the emergence of drug-resistant viruses in patients.

What are the project goals?

The major aims of this project are to characterize novel molecular mechanisms and protein-protein interactions that are key for herpesvirus assembly. The latter is a complex and highly regulated process including nuclear capsid assembly and genome packaging, nuclear egress, tegumentation in the cytoplasm, and capsid envelopment on cytoplasmic organelles. Each of these steps relies on essential, highly conserved, multimeric protein-protein interactions. Herpesvirus capsids assemble in the nucleus followed by genome packaging – a process mediated by a viral ternary protein complex called “terminase”. Subsequently, the mature capsids exit the nucleus via a specific nuclear escape mechanism that is driven by a viral protein complex called “nuclear egress complex”. Interactions of inner tegument proteins with the host cell’s microtubule transport machinery facilitate capsid transport to the site of final envelopment. We aim to synergize our diverse expertise on herpesvirus cell biology, protein functions, and structure to identify crucial protein-protein interactions that provide unique targets for novel anti-herpesviral therapy.

How do we get there?

We will focus on elucidating the underlying molecular principles how evolutionary conserved protein complexes function in herpesvirus assembly, and unite our unique expertise on crucial steps of herpesviral assembly (in collaboration with Thomas Schulz and Abel Viejo Borbolla). Combined, we have profound experience on sophisticated protein expression strategies, state-of-the-art structural biology (including X-ray crystallography, cryo electron microscopy, and electron cryo tomography), protein biochemistry (e.g. label-free interaction analysis, co-immuno-precipitation, in vitro capsid assembly and tegumentation), herpesvirus genetics (BAC mutagenesis), immunoelectron microscopy of infected cells and tissues, and life cell imaging using strains with fluorescently tagged capsids and tegument. With our broad expertise, we will uncover evolutionarily conserved mechanisms as well as steps that diverge in virus assembly among different herpesviruses.

Projectleaders D2

Project title: Herpesviral assembly

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

Prof. Dr. Thomas Krey

Projekte: B10, D1, D3

  Institut für Biochemie, Universität Lübeck
  Ratzeburger Allee 160
23562 Lübeck

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

Prof. Dr. Beate Sodeik

Projekte: A4, D2, D3

  Institut für Virologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-2846

Project D2 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 D2