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 stigmatizing 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

CV & Contact

Prof. Dr. Beate Sodeik

Projekte: A4, D2, D3

CV & Contact

Prof. Dr. Abel Viejo-Borbolla

Projekte: A3, A4

CV & Contact
Prof. Höglinger

Prof. Dr. Günter Höglinger

Projekte: A3, A4

CV & Contact

Prof. Dr. Ulrich Kalinke

Projekte: A4, B9

CV & Contact

Project A4 Publications

Publications of the Year 2021

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. doi: 10.1111/all.15120. Epub ahead of print. PMID: 34601735.

Eczema herpeticum in atopic dermatitis. Traidl S, Roesner L, Zeitvogel J, Werfel T.  Allergy. 2021 Oct;76(10):3017-3027. doi: 10.1111/all.14853. Epub 2021 May 3. PMID: 33844308.

Pathogenesis and virulence of herpes simplex virus. Zhu S, Viejo-Borbolla A. Virulence. 2021 Dec;12(1):2670-2702. doi: 10.1080/21505594.2021.1982373. PMID: 34676800.

Toll-like Receptors in Viral Encephalitis. Gern OL, Mulenge F, Pavlou A, Ghita L, Steffen I, Stangel M, Kalinke U.  Viruses. 2021 Oct 14;13(10):2065. doi: 10.3390/v13102065. PMID: 34696494.

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

Eczema herpeticum in atopic dermatitis. Traidl S, Rösner L, Zeitvogel J, Werfel T.  Allergy. 2021 Apr 12. doi: 10.1111/all.14853. Epub ahead of print. PMID: 33844308.

Publications of the Year 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. 2020 Sep 29;94(20):e01370-20. doi: 10.1128/JVI.01370-20. PMID: 32669337; PMCID: PMC7527038.

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.

Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease. Lang J, Bohn P, Bhat H, Jastrow H, Walkenfort B, Cansiz F, Fink J, Bauer M, Olszewski D, Ramos-Nascimento A, Duhan V, Friedrich SK, Becker KA, Krawczyk A, Edwards MJ, Burchert A, Huber M, Friebus-Kardash J, Göthert JR, Hardt C, Probst HC, Schumacher F, Köhrer K, Kleuser B, Babiychuk EB, Sodeik B, Seibel J, Greber UF, Lang PA, Gulbins E, Lang KS. Nat Commun. 2020 Mar 12;11(1):1338. doi: 10.1038/s41467-020-15072-8. PMID: 32165633; PMCID: PMC7067866.

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;117(32):19475-19486

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;140(8):1589-1598.e3

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;10:2553. doi: 10.3389/fimmu.2019.02553. eCollection 2019. Review.

STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus. Tegtmeyer PK, Spanier J, Borst K, Becker J, Riedl A, Hirche C, Ghita L, Skerra J, Baumann K, Lienenklaus S, Doering M, Ruzsics Z, Kalinke U. Nat Commun. 2019 Jun 27;10(1):2830. doi: 10.1038/s41467-019-10863-0.

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;16(1):248


Project A4