Which genetic factors lead to severe disease progressions? How does the virus manage to persist in the body permanently and what causes reactivation?

What is this research project about?

Human neurons infected with varicella zoster virus expressing a red fluorescent marker

What is this research project about?

Varicella zoster virus (VZV) infects the majority of people in industrialised countries. VZV establishes latency in neurons, remaining lifelong in the infected individual. Reactivation of VZV normally results in shingles, characterized by a painful rash, which may be followed by post-herpetic neuralgia (PHN), the second most common type of neuropathic pain worldwide. PHN is chronic pain that lasts for months after the disappearance of the rash and active VZV replication. Therefore, we hypothesise that VZV imposes epigenetic modifications in key genes involved in pain, leading to long-term changes in expression and activity even once VZV replication and expression has ended. Infection of the central nervous system may lead to encephalitis. Most individuals control VZV infection, whereas in others PHN or life-threatening diseases are more common. The mechanisms leading to latency and reactivation of VZV are unknown. Genetic polymorphisms, mainly affecting immune-related genes, may account for the different outcomes of infection. However, the relevance of most polymorphisms on VZV susceptibility has not been investigated.

What’s the current status?

Drugs to treat VZV disease target the lytic virus without affecting the latent reservoir. A newly developed subunit vaccine protects against zoster and subsequent chronic pain. However, the safety and efficacy of this vaccine has not been tested in most risk groups. Moreover, vaccination is far from universal. The identification of genetic polymorphisms responsible for severe VZV susceptibility and the mechanisms governing latency and reactivation will facilitate the development of drugs to alleviate exacerbated VZV disease.

Symbolbild Impfung

There is a vaccine that protects against zoster.

What are the project goals?

We want to answer the following questions:

  • Which are the host and viral genetic determinants responsible for VZV susceptibility?

  • Which are the mechanisms leading to latency and reactivation?

  • Can we identify biomarkers that predict the clinical sequelae after VZV reactivation?

Obtaining the answer to these questions will allow us to design novel therapeutic approaches to treat individuals suffering from exacerbated VZV-induced disease.

How do we get there?

We are a team of clinicians and basic researchers combining a wide range of scientific and technological expertise in the fields of virology, pathogenesis, neurology, dermatology and epigenetics, facilitating the success of the project.

We look into the proposed challenges from the perspective of the virus and the human being. VZV is a human specific virus that establishes latency and reactivates in neurons. Therefore, to investigate VZV and to develop and test hypotheses to inhibit establishment of latency and reactivation, it is necessary to use human neurons. To this end, we have derived human neurons from induced pluripotent stem cells (iPSC) and established VZV latency and reactivation models. With these models we have already started to investigate the process leading to VZV latency.
Our results show that the VZV genome is progressively repressed, inhibiting transcription of its genes. We have also established a collaboration with Trine Mogensen (Aarhus University, Denmark) to determine the role that genetic polymorphisms on RNA polymerase III have on VZV infection, latency and reactivation of human neurons.

For the clinical aims we are recruiting a cohort of patients with VZV reactivation that will be followed clinically and where biomaterials will be ascertained for a biomarker search. Our preliminary data suggest that a metabolomics analysis of the cerebrospinal fluid can predict the complicating involvement of the central nervous system. We will also use data from the HSV cohort. The samples of the RESIST study with the general population of Hannover will serve as a control here.

Expression of an axonal marker in human neurons


Project title: Identification and characterization of susceptibility factors for VZV Latency development and clinical course

Prof. Dr. Jochen Hühn

Projekte: A3, B1, RESIST-Kohorte

Prof. Dr. Thomas Werfel

Projekte: A3, A4, B5, RESIST-Kohorte

Prof. Dr. Abel Viejo-Borbolla

Projekte: A3, A4

Dr. Lennart Rösner

Projects: A3, A4, B5, RESIST-Cohort

Prof. Dr. Kurt-Wolfram Sühs

Projects: A3, A4

Project A3 Publications

Publications of the Year 2021:

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway. Luo Y, Möhn N, Skripuletz T, Senel M, Tumani H, Peßler F, Sühs KW, Stangel M. Ann Clin Transl Neurol. 2021 Dec;8(12):2228-2234. doi: 10.1002/acn3.51383. Epub 2021 Oct 8.

Elevated Free Phosphatidylcholine Levels in Cerebrospinal Fluid Distinguish Bacterial from Viral CNS Infections. Al-Mekhlafi A, Sühs KW, Schuchardt S, Kuhn M, Müller-Vahl K, Trebst C, Skripuletz T, Klawonn F, Stangel M, Pessler F.  Cells.

Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2. Zhu S, Stanslowsky N, Fernández-Trillo J, Mamo TM, Yu P, Kalmbach N, Ritter B, Eggenschwiler R, Ouwendijk WJD, Mzinza D, Tan L, Leffler A, Spohn M, Brown RJP, Kropp KA, Kaever V, Ha TC, Narayanan P, Grundhoff A, Förster R, Schambach A, Verjans GMGM, Schmidt M, Kispert A, Cantz T, Gomis A, Wegner F, Viejo-Borbolla A. Stem Cell Res.

Publications of the Year 2020:

Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis. de Araujo LS, Pessler K, Sühs KW, Novoselova N, Klawonn F, Kuhn M, Kaever V, Müller-Vahl K, Trebst C, Skripuletz T, Stangel M, Pessler F. J Transl Med.

Publications of the Year 2019:

Tau-protein concentrations are not elevated in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. Möhn N, Luo Y, Skripuletz T, Schwenkenbecher P, Zerr I, Lange P, Stangel M.  Fluids Barriers CNS.

Kynurenine Is a Cerebrospinal Fluid Biomarker for Bacterial and Viral Central Nervous System Infections Sühs KW, Novoselova N, Kuhn M, Seegers L, Kaever V, Müller-Vahl K, Trebst C, Skripuletz T, Stangel M, Pessler F.  J Infect Dis.

Current In Vitro Models to Study Varicella Zoster Virus Latency and Reactivation. Baird NL, Zhu S, Pearce CM, Viejo-Borbolla A. Viruses.

Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis. Ratuszny D, Sühs KW, Novoselova N, Kuhn M, Kaever V, Skripuletz T, Pessler F, Stangel M.  Int J Mol Sci.

Severe Progressive Multifocal Leukoencephalopathy (PML) and Spontaneous Immune Reconstitution Inflammatory Syndrome (IRIS) in an Immunocompetent Patient. Krey L, Raab P, Sherzay R, Berding G, Stoll M, Stangel M, Wegner F. Front Immunol

Publications of the Project A3