Adler Lab

Head of lab

Prof. Dr. med. vet. Heiko Adler

Scientific Focus

Synergies between viral infection and toxic exposures for lung diseases

The human gammaherpesviruses Epstein-Barr Virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are associated with a number of tumors and lymphoproliferative disorders. In addition, gammaherpesviruses are believed to be causally involved in a number of chronic diseases including chronic lung diseases. Due to the species-specificity of the gammaherpesviruses, pathogenetic studies of the human infections are restricted. Murine gammaherpesvirus 68 (MHV-68), a rodent gammaherpesvirus, allows to study the pathogenesis of a gammaherpesvirus infection in the mouse, a model that is amenable to genetic manipulation. In our research projects, we use MHV-68 infection of mice to study gammaherpesvirus pathogenesis, in particular the role of gammaherpesvirus infection in the pathophysiology of chronic lung diseases.

Main Projects

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1) Virus-induced model of idiopathic pulmonary fibrosis (IPF)

We use MHV-68 infection of mice to investigate virus-induced pulmonary fibrosis. Specifically, we i) study the pathophysiology of IPF, ii) determine molecular mechanisms involved in disrepair of the injured lung and iii) test and define novel therapeutic strategies.

2) Interaction of herpesviruses with environmental pollutants (in cooperation with Dr. T. Stoeger, Helmholtz Munich)

We investigate the interaction between environmental pollutants and persistent virus infection. For example, inhalation of nanoparticles (NP) is known to trigger adverse reactions in the respiratory system, e.g. increased rates of chronic pulmonary diseases like COPD exacerbations for traffic emissions, or even cancer and fibrosis for respirable fibers. Several studies imply that herpesvirus infection may contribute to the development of pulmonary fibrosis. Since every human being is persistently infected with herpesviruses, we propose that the combination of NP exposure and persistent virus infection may result in chronic lung disease. Therefore, we investigate whether the interaction between NP and virus infection leads to more severe disease than exposure to each factor alone. We will determine the underlying molecular mechanisms and subsequently try to develop novel therapeutic strategies.

3) Virus infection as second hit on pre-existing endogenous injuries (in cooperation with Prof. A. Guenther, Universities of Giessen and Marburg Lung Centre)

A hallmark of idiopathic pulmonary fibrosis (IPF) is endoplasmic reticulum (ER) stress and apoptosis in type-II alveolar epithelial cells (AECII). In this project, we investigate MHV-68 infection in transgenic mice with AECII-specific Chop overexpression. Specifically, we will analyze whether this mouse model develops lung fibrosis in the absence or presence of MHV-68 infection as a second profibrotic stimulus.

4) The role of Transient Receptor Potential (TRP) channels in virus-induced lung fibrosis (in cooperation with Prof. A. Dietrich, Walther Straub Institute of Pharmacology and Toxicology)

Several TRP channels are expressed in the respiratory tract where they have multiple functions in a variety of cells both under healthy and diseased conditions, e.g. in pulmonary fibrosis. In this project, we want to investigate the combined effect of dysregulated TRP channel functions and virus infection on the development of chronic lung diseases.

5) Viral infections in neonatal chronic lung disease (in cooperation with Prof. A. Hilgendorff, Carl von Ossietzky University Oldenburg)

Prematurely born infants require prolonged oxygen supplementation and/or mechanical ventilation due to the functional and structural immaturity of their lungs. Although life-saving, the outlined treatment regimen, especially in the context of pre- and postnatal infections, can lead to the development of Bronchopulmonary Dysplasia (BPD), the neonatal form of chronic lung disease. The disease is characterized by impaired development of the gas exchange area including extensive matrix remodeling together with pulmonary inflammation and altered growth factor signaling. In this project, we investigate the role of viral infections in the development of BPD.

Selected Publications

H. Adler, Beland, J.L., Del-Pan, N.C., Kobzik, L., Brewer, J., Martin, T.R. and Rimm, I. J.: Suppression of Herpes simplex virus type 1 (HSV-1) induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2). (Journal of Experimental Medicine, 185 (1997): 1533-1540)

H. Adler, Beland, J.L., Kozlow, W., Del-Pan, N.C., Kobzik, L., and Rimm, I.J.: A role for transforming growth factor-beta 1 in the increased pneumonitis in murine allogeneic bone marrow transplant recipients with graft-versus-host disease after pulmonary herpes simplex virus-type 1 infection. (Blood, 92 (1998): 2581-2589)

H. Adler, Messerle, M., Wagner, M., and Koszinowski, U.H.: Cloning and mutagenesis of the murine gammaherpesvirus 68 genome as an infectious bacterial artificial chromosome. (Journal of Virology, 74 (2000): 6964-6974)

P.G. Stevenson, J.S. May, X.G. Smith, S. Marques, H. Adler, U.H. Koszinowski, J.P. Simas, and Efstathiou, S.: K3-mediated evasion of CD8+ T cells aids amplification of a latent g-herpesvirus (Nature Immunology, 3 (2002): 733-740).

S. Andreansky, H. Liu, H. Adler, U.H. Koszinowski, S. Efstathiou, and P.C. Doherty: The limits of protection by “memory” T cells in Ig-/- mice persistently infected with a g-herpesvirus (Proceedings of the National Academy of Sciences of the USA, 101 (2004): 2017-2022).

W. V. Bonilla, A. Fröhlich, K. Senn, S. Kallert, M. Fernandez, S. Johnson, M. Kreutzfeldt, A. N. Hegazy, C. Schrick, P. G. Fallon, R. Klemenz, S. Nakae, H. Adler, D. Merkler, M. Löhning and D. D. Pinschewer: The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses (Science, 335 (2012): 984-989. doi: 10.1126/science.1215418).

C. Sattler, B. Steer, and H. Adler: Multiple lytic origins of replication are required for optimal gammaherpesvirus fitness in vitro and in vivo (PLoS Pathogens, 12 (3) (2016): e1005510. doi: 10.1371/journal.ppat.1005510).

C. Sattler, F. Moritz, S. Chen, B. Steer, D. Kutschke, M. Irmler, J. Beckers, O. Eickelberg, P. Schmitt-Kopplin, H. Adler* and T. Stoeger*: Nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection (Particle and Fibre Toxicology, 14 (2017): 2. doi: 10.1186/s12989-016-0181-1). * (shared last authorship)

C.G.K. Ziegler, Allon, S.J., […], Adler, H., […], Shalek, A.K., Ordovas-Montanes, J., HCA Lung Biological Network: SARS-CoV-2receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. (Cell (2020): 181(5): 1016-1035.e19. doi: 10.1016/j.cell.2020.04.035).

J.D. Speidel, S. Gilles, B. Steer, B. Vafadari, D. Rauer, C. Traidl-Hoffmann, and H. Adler: Pollen induce reactivation of latent herpesvirus and differentially affect infected and uninfected murine macrophages. (Allergy (2021): 76(5): 1539-1542. doi: 10.1111/all.14587).

L. Han, V. Haefner, Y. Yu, B. Han, H. Ren, M. Irmler, J. Beckers, Q. Liu, A. Feuchtinger, A. O. Yildrim, H. Adler*, T. Stoeger*: Nanoparticle exposure triggered virus reactivation induces lung emphysema in mice. (ACS Nano (2023): https://doi.org/10.1021/acsnano.3c04111). * (shared last authorship)