Which mechanisms lead to severe disease progression after herpes infections in humans with atopic dermatitis?

What is this research project about?

Fluoreszenzmikroskopie einer mit Varizella Zoster Viren infizierten menschlichen Zelle

Fluorescence microscopy of a human cell infected with Varizella Zoster viruses.

What is this research project about?

The human alpha herpesviruses herpes simplex virus type 1 (HSV-1), HSV-2 and Varicella Zoster Virus (VZV) cause diseases ranging from painful and stigmatising facial, oral and genital lesions to life-threating encephalitis, meningitis, and disseminating infections. Primary and recurrent infections cause significant morbidity and even mortality particularly in individuals with increased susceptibility, either due to genetic factors or to immune suppression, as well as very early in life and in the elderly. HSV and VZV are the most common infections of the human nervous system, affecting mostly the peripheral nervous system but also infecting the brain. The long-term post-herpetic neuralgia impairs the quality of life for several months to years after an active zoster episode (shingles). Atopic, so-called “allergic”, skin inflammation leads to vulnerability of the skin and increased susceptibility to viral infections can be observed. Disseminating spread of HSV in the skin (eczema herpeticum, EH) can be life threatening and is a common cause for hospitalization of a severely affected subgroup of patients with atopic dermatitis (AD).

What’s the current status?

While several effective drugs such as acyclovir which block viral replication are available to treat infection with alpha herpesviruses, they often can only be applied too late after a full outbreak of clinical symptoms. However, levels in the brain are often too low to be sufficiently effective and patients with disseminated HSV skin infections are at risk for severe complications including herpes encephalitis.

In this project, we want to elucidate why a subgroup of patients suffers particularly from increased susceptibility to HSV and VZV infections, in order to develop new concepts and novel therapeutic strategies. In earlier studies, we generated primary human skin cells (keratinocytes) from hair follicles of patients who suffered from AD, and who had a history of EH (AD/EH). We compared the HSV-1 infection rates in cells from AD/EH patients with those from AD patients without previous EH and to healthy controls. The data clearly indicate that keratinocytes from the EH patients were most susceptible to HSV-1 infection. In former studies we saw that the skin inflammation in AD contributes to a weakened skin barrier function (Seltmann et al. 2015), and to an increased susceptibility to viruses (Traidl et al. 2018). To identify genetic risk factors, we collect patient samples (to date: more than 1,000 patients with chronic cutaneous inflammatory diseases including 500 AD patients), and we perform genetic analyses of patients suffering from AD and with a history of EH.

Sensory neurons that expose markers

What are the project goals?

We aim to understand the mechanisms of increased susceptibility to HSV and VZV in patients and in different cell types including skin cells, neurons, immune cells and the interaction between them.

How do we get there?

We are in a unique position to identify novel primary immune deficiency factors increasing the susceptibility to alpha herpesvirus infections and leading to adverse disease progression. We combine complementary expertise on skin diseases, immunology, clinical neurology, virology, cell biology, and in particular, the combined genetic contribution of the host and the pathogens involved.

Our experience in cell culture systems to study the most relevant cell types for alpha herpesvirus infection; namely, keratinocytes, fibroblasts, immune cells and neurons will help us to build up experimental models to investigate different factors leading to enhanced susceptibility to viruses. We will determine whether the candidate factors identified through the patient cohort induce increased susceptibility to HSV-1 and -2, VZV, smallpox vaccination (MVA), or rhinovirus (RSV).

Towards this end, we develop a murine skin infection model to study the dynamics of HSV-1 spread within the skin, and from the skin to the nervous system. In this system, we will be able to manipulate potential host susceptibility factors, and to study their impact on the progression of viral skin infection. In addition, samples are currently being collected for the HSV cohort.

Electron microscope image of a capsid of the herpes simplex virus


Project title: Host determinants of severe herpes infections in atopic dermatitis

Prof. Dr. Thomas Werfel

Projekte: A3, A4, B5, RESIST-Kohorte

Prof. Dr. Beate Sodeik

Projekte: A4, D1, D2

Prof. Dr. Abel Viejo-Borbolla

Projekte: A3, A4

Prof. Dr. Ulrich Kalinke

Projekte: A4, B9

Dr. Lennart Rösner

Projects: A3, A4, B5, RESIST-Cohort

Prof. Dr. Kurt-Wolfram Sühs

Projects: A3, A4

Project A4 Publications

Publications of the Year 2023

High recurrence rate of eczema herpeticum in moderate/severe atopic dermatitis -TREATgermany registry analysis. Hohe Rezidivrate des Eczema herpeticatum bei mittelschwerer bis schwerer atopischer Dermatitis – eine TREATgermany Registeranalyse  Traidl S, Heinrich L, Siegels D, Rösner L, Haufe E, Harder I, Abraham S, Ertner K, Kleinheinz A, Schäkel K, Wollenberg A, Effendy I, Quist S, Asmussen A, Wildberger J, Weisshaar E, Wiemers F, Brücher JJ, Weidinger S, Schmitt J, Werfel T; J Dtsch Dermatol Ges. 2023 Dec;21(12):1490-1498. First published: 11 December 2023 https://doi.org/10.1111/ddg.15205_g

Inhibition of IL-17 ameliorates keratinocyte-borne cytokine responses in an in vitro model for house-dust-mite triggered atopic dermatitis. Haertlé J, Kienlin P, Begemann G, Werfel T, Roesner LM. Sci Rep. 2023 Oct 3;13(1):16628.

Dupilumab strengthens herpes simplex virus type 1-specific immune responses in atopic dermatitis. Traidl S, Harries L, Kienlin P, Begemann G, Roesner LM, Werfel T. J Allergy Clin Immunol. 2023 Sep 1:S0091-6749(23)01106-5.

Colonization of peripheral ganglia by herpes simplex virus type 1 and 2; Kai A Kropp, Guorong Sun, Abel Viejo-Borbolla Current Opinion in Virology, Volume 60, June 2023, 101333

Publications of the Year 2022

T-cell receptor sequencing specifies psoriasis as a systemic and atopic dermatitis as a skin-focused, allergen-driven disease. Roesner LM, Farag AK, Pospich R, Traidl S, Werfel T.  Allergy. 2022 Sep;77(9):2737-2747. Epub 2022 Mar 14.

Single-cell profiles reveal distinctive immune response in atopic dermatitis in contrast to psoriasis. Zhang B, Roesner LM, Traidl S, Koeken VACM, Xu CJ, Werfel T, Li Y. Allergy. 2022 Aug 20.

An integrated analysis of herpes virus infections from eight randomised clinical studies of baricitinib in adults with moderate to severe atopic dermatitis.  Werfel T, Irvine AD, Bangert C, Seneschal J, Grond S, Cardillo T, Brinker D, Zhong J, Riedl E, Wollenberg A. J Eur Acad Dermatol Venereol. 2022 Sep; Epub 2022 May 18.

Specific T cells targeting Staphylococcus aureus fibronectin-binding protein 1 induce a type 2/type 1 inflammatory response in sensitized atopic dermatitis patients. Farag AK, Roesner LM, Wieschowski S, Heratizadeh A, Eiz-Vesper B, Kwok WW, Valenta R, Werfel T.  Allergy. 2022 Apr;77(4):1245-1253.

Specific IgE against the house dust mite allergens Der p 5, 20 and 21 influences the phenotype and severity of atopic diseases. Walsemann T, Böttger M, Traidl S, Schwager C, Gülsen A, Freimooser S, Roesner LM, Werfel T, Jappe U. Allergy. 2022 Oct 14.

Diversities of allergic pathologies and their modifiers: Report from the second DGAKI-JSA meeting. Asano K, Tamari M, Zuberbier T, Yasudo H, Morita H, Fujieda S, Nakamura Y, Traidl S, Hamelmann E, Raap U, Babina M, Nagase H, Okano M, Katoh N, Ebisawa M, Renz H, Izuhara K, Worm M. Allergol Int.

Publications of the Year 2021

Pathogenesis and virulence of herpes simplex virus. Zhu S, Viejo-Borbolla A. Virulence. 2021 Dec;12(1):2670-2702.

Perception of the coronavirus pandemic by patients with atopic dermatitis – Results from the TREATgermany registry. Helmert C, Siegels D, Haufe E, Abraham S, Heratizadeh A, Kleinheinz A, Harder I, Schäkel K, Effendy I, Wollenberg A, Sticherling M, Stahl M, Worm M, Schwichtenberg U, Schwarz B, Rossbacher J, Buck PM, Schenck F, Werfel T, Weidinger S, Schmitt J; TREATgermany Study Team. J Dtsch Dermatol Ges. 2021 Dec 27.

Specific T cells targeting Staphylococcus aureus fibronectin-binding protein 1 induce a type 2/type 1 inflammatory response in sensitized atopic dermatitis patients. Farag AK, Roesner LM, Wieschowski S, Heratizadeh A, Eiz-Vesper B, Kwok WW, Valenta R, Werfel T. Allergy. 2021 Oct 3.

Eczema herpeticum in atopic dermatitis. Traidl S, Roesner L, Zeitvogel J, Werfel T.  Allergy. 2021 Oct; Epub 2021 May 3.

Toll-like Receptors in Viral Encephalitis. Gern OL, Mulenge F, Pavlou A, Ghita L, Steffen I, Stangel M, Kalinke U.  Viruses. 2021 Oct 14.

Free human DNA attenuates the activity of antimicrobial peptides in atopic dermatitis. Kopfnagel V, Dreyer S, Zeitvogel J, Pieper DH, Buch A, Sodeik B, Rademacher F, Harder J, Werfel T. Allergy. 2021 Jun 27. doi: 10.1111/all.14992. Online ahead of print. PMID: 34176149

Atopic Eczema: Pathophysiological Findings as the Beginning of a New Era of Therapeutic Options. Traidl S, Werfel T, Traidl-Hoffmann C. Handb Exp Pharmacol. 2021 Jul 9. doi: 10.1007/164_2021_492. Online ahead of print. PMID: 34236520

Sequential MAVS and MyD88/TRIF signaling triggers anti-viral responses of tick-borne encephalitis virus-infected murine astrocytes. Ghita L, Breitkopf V, Mulenge F, Pavlou A, Gern OL, Durán V, Prajeeth CK, Kohls M, Jung K, Stangel M, Steffen I, Kalinke U. J Neurosci Res. 2021 Jul 23. doi: 10.1002/jnr.24923. Online ahead of print. PMID: 34296786

Beneficial and detrimental functions of microglia during viral encephalitis. Waltl I, Kalinke U.  Trends Neurosci. 2021 Dec 11:S0166-2236(21)00233-2.

Janus kinase inhibitors for the therapy of atopic dermatitis. Traidl S, Freimooser S, Werfel T.  Allergol Select. 2021 Aug 27;5:293-304. doi: 10.5414/ALX02272E. PMID: 34532638; PMCID: PMC8439108.

Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly. Krenn V, Bosone C, Burkard TR, Spanier J, Kalinke U, Calistri A, Salata C, Rilo Christoff R, Pestana Garcez P, Mirazimi A, Knoblich JA. Cell Stem Cell. 2021 Aug 5;28(8):1362-1379.e7. doi: 10.1016/j.stem.2021.03.004. Epub 2021 Apr 9. PMID: 33838105; PMCID: PMC7611471.

Publications of the Year 2020

HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection. Bodda C, Reinert LS, Fruhwürth S, Richardo T, Sun C, Zhang BC, Kalamvoki M, Pohlmann A, Mogensen TH, Bergström P, Agholme L, O’Hare P, Sodeik B, Gyrd-Hansen M, Zetterberg H, Paludan SR.  J Exp Med. 2020 Jul 6;217(7):e20191422.

Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner. Kropp KA, López-Muñoz AD, Ritter B, Martín R, Rastrojo A, Srivaratharajan S, Döhner K, Dhingra A, Czechowicz JS, Nagel CH, Sodeik B, Alcami A, Viejo-Borbolla A. J Virol. 2020 Sep 29

Recurrent eczema herpeticum – a retrospective European multicenter study evaluating the clinical characteristics of eczema herpeticum cases in atopic dermatitis patients. Seegräber M, Worm M, Werfel T, Svensson A, Novak N, Simon D, Darsow U, Augustin M, Wollenberg A. J Eur Acad Dermatol Venereol. 2020 May;34(5):1074-1079. doi: 10.1111/jdv.16090. Epub 2020 Jan 30. PMID: 31733162.

Absence of cGAS-mediated type I IFN responses in HIV-1-infected T cells Elsner C, Ponnurangam A, Kazmierski J, Zillinger T, Jansen J, Todt D, Döhner K, Xu S, Ducroux A, Kriedemann N, Malassa A, Larsen PK, Hartmann G, Barchet W, Steinmann E, Kalinke U, Sodeik B, Goffinet C.  Proc Natl Acad Sci U S A 2020

RNase 7 promotes sensing of self-DNA by human keratinocytes and activates an antiviral immune response Kopfnagel V, Dreyer S, Baumert K, Stark M, Harder J, Hofmann K, Kleine M, Buch A, Sodeik B, Werfel T.  J Invest Dermatol 2020

Publications of the Year 2019

The Antimicrobial and Immunomodulatory Function of RNase 7 in Skin. Rademacher F, Dreyer S, Kopfnagel V, Gläser R, Werfel T, Harder J. Front Immunol. 2019 Nov 5

Recurrent Eczema Herpeticum – A Retrospective European Multicenter Study Evaluating the Clinical Characteristics of Eczema Herpeticum Cases in Atopic Dermatitis Patients. Seegräber M, Worm M, Werfel T, Svensson A, Novak N, Simon D, Darsow U, Augustin M, Wollenberg A. J Eur Acad Dermatol Venereol 2020

Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner. Kropp KA, López-Muñoz AD, Ritter B, Martín R, Rastrojo A, Srivaratharajan S, Döhner K, Dhingra A, Czechowicz JS, Nagel CH, Sodeik B, Alcami A, Viejo-Borbolla A. J Virol.

HSV-1 triggers paracrine fibroblast growth factor response from cortical brain cells via immediate-early protein ICP0 Hensel N, Raker V, Förthmann B, Detering NT, Kubinski S, Buch A, Katzilieris-Petras G, Spanier J, Gudi V, Wagenknecht S, Kopfnagel V, Werfel TA, Stangel M, Beineke A, Kalinke U, Paludan SR, Sodeik B, Claus P.  J Neuroinflammation 2019;

Publications of the Project A4