Innate Immunity
The Innate Immunity research group investigates the mechanisms by which microbes and microbial structures activate the innate immune system. Our work focuses on the interaction and communication between epithelial and dendritic cells - both among themselves and with the adaptive immune system - and on how these processes influence chronic lung diseases such as asthma and COPD.
Our research focuses on the activation of the innate immune system and its crosstalk with adaptive immunity. In particular, we study the airway epithelium as the first contact zone for microbes and dendritic cells as key mediators of adaptive immune activation.
We are especially interested in allergy-protective bacteria and archaea. Archaea differ fundamentally from bacteria—they possess a distinct cell structure and employ unique metabolic pathways (e.g., methane formation in methanogenic archaea).
We aim to elucidate the molecular mechanisms by which these microorganisms activate the innate immune system and thereby influence chronic lung diseases such as asthma, allergies, and COPD. These insights may serve as the basis for developing novel preventive and therapeutic strategies.
Can early-life exposure to microbes protect against later allergies?
In the field of allergy prevention, we have been studying for several years the molecular mechanisms by which bacteria isolated from cowshed environments confer protection against asthma and allergic inflammation. Using various models, we demonstrated that these protective effects are mediated by the activation of distinct cellular signaling pathways (Debarry et al. 2007, 2010; Hagner et al. 2013; Stein et al. 2017).
In recent years, it has become evident that even the innate immune system can develop a form of memory—known as trained immunity—through epigenetic and metabolic reprogramming of cells. We investigate the extent to which trained immunity contributes to the protective effects of certain bacteria and how this mechanism could be harnessed for targeted preventive strategies.
To induce defined innate immune responses, we have been collaborating for many years with Alla Zamyatina’s group (BoKu Vienna), who develops synthetic, glycan-based biomolecules derived from natural templates. These structures can act as either agonists or antagonists and may serve as adjuvants (Garate et al. 2015; Adanitsch et al. 2018; Borio et al. 2018; Strobl et al. 2022, 2024; Borio et al. 2023; Fu et al. 2025).
Archaea – Unexplored Modulators of the Immune System
While bacteria and their metabolites have long been the focus of immunological research, the immunomodulatory potential of archaea remains largely unexplored. Although they share morphological similarities with bacteria, archaea differ substantially in the biochemical composition of their cell envelopes. Microbiome studies have revealed that various archaeal species - due to their unique metabolic features - constitute an integral part of the human microbiota.
We have shown that archaea interact specifically with components of the human immune system and can contribute to maintaining immune homeostasis (Bang et al. 2014, 2017; Vierbuchen et al. 2017; Kuehnast et al. 2024). Currently, we are investigating the molecular basis of interactions between methanoarchaeal strains (e.g., Methanobrevibacter smithii and Methanosphaera stadtmanae) and human immune and epithelial cells, aiming to identify the archaeal molecules involved and the activated signaling pathways in host cells.
The Human Microbiome and Archaea
The composition of the human microbiome has been the subject of intense research in recent years. Most studies, however, focus on bacteria. Although archaea represent a quantitatively smaller fraction of the microbiota, they play a crucial functional role due to their unique metabolic characteristics. Within the ALLIANCE cohort of the German Center for Lung Research (DZL), we examine whether the presence of different archaeal species correlates with the occurrence of diseases such as asthma.
By analyzing both the immunological activity of distinct archaeal species and their contribution to the human microbiome, we aim to better understand the role of archaea in trained immunity.
Ministry of Education and Science
- Member of Deutsches Zentrum für Lungenforschung (DZL), Airway Research Center North (ARCN): 1. Disease Area Asthma/Allergy (PI: Holger Heine)
DFG
- HE 2758/6-1 "Archaeome-Immunsystem-Interaktionen"
- Dendritic cells (human and mouse)
- Transient transfection, focus on receptors and adaptor molecules of the ionnaste immune system (TLRs, NLRs)
- Real-time PCR (Lightcycler 2.0, Lightcycler480)
- ChIP
- FACS
- Confocal Microscopy
- Generation of knockout cell lines in human bronchial epithelial- and monocyte-like cells by CRISPR/Cas
2025
Bossen, J, Knop, M, Niu, X, Thiedmann, M, Prange, R, Tahanzadeh, N, Franzenburg, S, Bruchhaus, I, Heine, H & Roeder, T 2025, 'Chronic airway inflammation in Drosophila lacking the A20-like protein Trabid', FRONTIERS IN IMMUNOLOGY, Jg. 16, S. 1564386. https://doi.org/10.3389/fimmu.2025.1564386
Fu, Y, Kim, H, Lee, DS, Han, A-R, Heine, H, Zamyatina, A & Kim, HM 2025, 'Structural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes', Nature communications, Jg. 16, Nr. 1, S. 4164. https://doi.org/10.1038/s41467-025-59550-3
Krause, K, Franch Arroyo, S, Ugolini, M, Kueck, T, Sullivan, TJ, Gálvez, EJC, Muenzner, M, Goosmann, C, Brinkmann, V, Frese, CK, Alagesan, K, Vierbuchen, T, Heine, H, Resch, U, Sander, LE & Charpentier, E 2025, 'Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes', EMBO REPORTS . https://doi.org/10.1038/s44319-025-00558-7
Nitschkowski, D, Vierbuchen, T, Heine, H, Behrends, J, Reiling, N, Reck, M, Rabe, KF, Kugler, C, Ammerpohl, O, Drömann, D, Muley, T, Kriegsmann, M, Stathopoulos, GT, Arendt, KAM, Goldmann, T & Marwitz, S 2025, 'SMAD2 linker phosphorylation impacts overall survival, proliferation, TGFβ1-dependent gene expression and pluripotency-related proteins in NSCLC', BRITISH JOURNAL OF CANCER . https://doi.org/10.1038/s41416-025-02970-1
2024
Kuehnast, T, Kumpitsch, C, Mohammadzadeh, R, Weichhart, T, Moissl-Eichinger, C & Heine, H 2024, 'Exploring the human archaeome: its relevance for health and disease, and its complex interplay with the human immune system', The FEBS journal. https://doi.org/10.1111/febs.17123
Metwally, NG, Tauler, MDPM, Torabi, H, Allweier, J, Mohamed, S, Bessemoulin, M, Bouws, P, Alshikh, F, Wu, Y, Temori, M, Schell, T, Rakotonirinalalao, M, Honecker, B, Höhn, K, Jacobs, T, Heine, H & Bruchhaus, I 2024, 'Distinct brain and lung endothelial miRNA/mRNA profiles after exposure to Plasmodium falciparum-infected red blood cells', iScience, Jg. 27, Nr. 11, S. 111265. https://doi.org/10.1016/j.isci.2024.111265
Zamyatina, A, Strobl, S, Zucchetta, D, Vasícek, T, Alessandro, M, Ruda, A, Widmalm, G & Heine, H 2024, 'Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4-specific LPS Mimetics with Picomolar Potency', ANGEWANDTE CHEMIE-INTERNATIONAL EDITION , Jg. 63, Nr. 39, S. e202408421. https://doi.org/10.1002/anie.202408421
2023
Borio, A, Holgado, A, Passegger, C, Strobl, H, Beyaert, R, Heine, H & Zamyatina, A 2023, 'Exploring Species-Specificity in TLR4/MD-2 Inhibition with Amphiphilic Lipid A Mimicking Glycolipids', Molecules (Basel, Switzerland), Jg. 28, Nr. 16. https://doi.org/10.3390/molecules28165948
Vierbuchen, T, Agarwal, S, Johnson, JL, Galia, L, Lei, X, Stein, K, Olagnier, D, Gaede, KI, Herzmann, C, Holm, CK, Heine, H, Pai, A, O'Hara Hall, A, Hoebe, K & Fitzgerald, KA 2023, 'The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Jg. 120, Nr. 1, S. e2213715120. https://doi.org/10.1073/pnas.2213715120
Volkmar, K, Jaedtka, M, Baars, I, Walber, B, Philipp, M-S, Bagola, K, Müller, AJ, Heine, H & van Zandbergen, G 2023, 'Investigating pyroptosis as a mechanism of L. major cell-to-cell spread in the human BLaER1 infection model', MOLECULAR MICROBIOLOGY. https://doi.org/10.1111/mmi.15142
2022
Heine, H & Zamyatina, A 2022, 'Therapeutic Targeting of TLR4 for Inflammation, Infection, and Cancer: A Perspective for Disaccharide Lipid A Mimetics', Pharmaceuticals (Basel, Switzerland), Jg. 16, Nr. 1, 23. https://doi.org/10.3390/ph16010023
Köllisch, G, Solis, FV, Obermann, H-L, Eckert, J, Müller, T, Vierbuchen, T, Rickmeyer, T, Muche, S, Przyborski, JM, Heine, H, Kaufmann, A, Baumeister, S, Lingelbach, K & Bauer, S 2022, 'TLR8 is activated by 5'-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway', Cell reports, Jg. 39, Nr. 2, S. 110691. https://doi.org/10.1016/j.celrep.2022.110691
Sirocko, K-T, Angstmann, H, Papenmeier, S, Wagner, C, Spohn, M, Indenbirken, D, Ehrhardt, B, Kovacevic, D, Hammer, B, Svanes, C, Rabe, KF, Roeder, T, Uliczka, K & Krauss-Etschmann, S 2022, 'Early-life exposure to tobacco smoke alters airway signaling pathways and later mortality in D. melanogaster', Environmental pollution (Barking, Essex : 1987), Jg. 309, S. 119696. https://doi.org/10.1016/j.envpol.2022.119696
Strobl, S, Hofbauer, K, Heine, H & Zamyatina, A 2022, 'Lipid A mimetics based on unnatural disaccharide scaffold as potent TLR4 agonists for prospective immunotherapeutics and adjuvants', Chemistry (Weinheim an der Bergstrasse, Germany), Jg. 28, Nr. 35, e202200547, S. e202200547. https://doi.org/10.1002/chem.202200547
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