General Information and list of ongoing projects

The incidence and prevalence of immune mediated inflammatory diseases (IMIDs) are steadily increasing. Unfortunately, most therapies used against these diseases have as of yet palliative character and mostly do not offer a cure. Thus life-long treatment using immune-suppressive agents is required in the majority of cases. As a consequence, patients with IMID must live with side effects of these treatments, such as increased risk of opportunistic infections and relapsing flares of the disease itself. Furthermore, chronic inflammation can also promote the development of certain forms of cancer. For example, it has been observed that inflammatory bowel disease (IBD) is associated with an increased risk of developing colorectal cancer, especially in patients suffering from chronic uncontrolled intestinal inflammation. Therefore, there is major need for new therapies, which can modulate the immune response more specifically.

Recent studies by others and by our group have shown that a specific subset of CD4 T cells, the TH17 cells, and their associated cytokines play an important but ambiguous role in these diseases. These cells are known to play a key role in chronic inflammatory diseases and carcinogenesis. But on the other hand, these same cells and their cytokine products, such as IL-22, also have beneficial properties, like promotion of wound healing and defence against pathogens. This obviously reveals that it is crucial to find out the molecular and cellular mechanisms, which physiologically control TH17 cells. The main goal is to develop therapies which would not just simply deplete them, but rather reset them to their beneficial state. We have indeed already identified several mechanisms, which explain how TH17 cells and their cytokines can be physiologically controlled. Strikingly, we have found that the intestine is an organ which plays a major role in controlling the immunological process. We refer to this concept as Intestinal Immune Regulation, where we propose that the intestine is indeed one of the controlling centers of the immune system and in turn, of the systemic homeostasis. In support of this, we found that TH17 cells can be recruited to the intestine, where they are then controlled by Foxp3+ regulatory T cells (Tregs) and T regulatory type 1 cells (Tr1) via IL-10. Furthermore, TH17 cells can also acquire regulatory properties and can convert into Tr1 cells in the intestine. Finally, IL-22, a key cytokine produced by TH17 cells, can be controlled via a soluble inhibitor, namely IL-22 binding protein (IL-22BP). As described above, however, TH17 cells are one of the causes of several immune mediated diseases in several different organs, such as kidney and central nervous system (CNS). This usually results from a failure of the physiological regulatory mechanisms which are in place, especially in the intestine. We were indeed able to show in mouse models that the Intestinal Immune Regulation can also actually be used to prevent and treat diseases in peripheral organs. Thus, we are working on the hypothesis that the Intestinal Immune Regulation can be targeted for a wide variety of inflammatory diseases.

List of ongoing research topics

• Regulation of TH17 cell migration from several other organs to the intestine and vice versa.

• Tissue specific control of TH17 cells by regulatory T cells.

• Modulation of TH17 cell phenotype, stability and plasticity.

• Identifying the network controlling the IL-22 – IL-22BP axis for targeted therapies

• Basic and translational research aiming to validate the role of the Intestinal Immune Regulation in IBD, Hepatitis, Nephritis, Multiple Sclerosis, and intestinal carcinogenesis.

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Objectives

Our long-term goal is to further explore and prove the hypothesis that the intestine serves as a key organ in regulating immune responses. Initially the thymus and the bone marrow were thought to be the sole control center with the ability to set or reset the immune system. In the last years however, we and others have revealed that the intestine is a key organ, which is able to finely-tune the immune system. Furthermore, this regulation also affects diseases in other peripheral organs. Thus, we hypothesize that by controlling the intestinal immune system we can prevent or cure chronic inflammatory and autoimmune diseases in seemingly unrelated organs, such as the CNS, liver and kidney. This hypothesis is based on recent findings by others and by us showing that the intestine plays a key role in modulating the balance between regulatory T cells, such as Foxp3+ Treg, Tr1 cells, and effector T cells, thereby influencing Immune-mediated inflammatory diseases in several organs. However, most T cells and cytokines have both context dependent pathogenic and protective functions. The right balance must be achieved. Thus, one key aspect of our study is to dissect complex biological systems in order to regulate rather than to block immune responses in order to facilitate the beneficial functions of these cells.

On the basis of our previous work we are working on four connected but independent projects as shown in Figure 1.

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Methods

General experimental approach

The aim of our studies is to dissect complex biological systems regulating inflammation, tissue regeneration and carcinogenesis. In order to do so, we are using a step-by-step approach (Figure 2). First, we reduce a complex system to a few key factors. In particular, we break down the complexity of the system to the T cells, cytokines, microbiota, and tissues. Using a reductionist approach, we then try to understand how each factor contributes to the overall picture, depicted in Figure 2 as a house. After that, we formulate a working hypothesis which still needs to hold through in the original complex system. This will be achieved by combining the analysis of knock in and knock out mice, mouse models for human diseases and tissue samples from patients suffering from these diseases.

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Mouse Models

We are currently maintaining a variety of well-defined transgenic mouse lines, which are important for our research projects. These include several knock in reporter mice, conditional and total knock out strains for example for IL-22, IL-22BP, and IL-22R1. Below is a list of selected mouse lines, which play key roles in the proposed projects.

Mouse Models of intestinal inflammation, tissue damage and carcinogenesis

We are using well-established mouse models for intestinal inflammation, tissue damage and carcinogenesis. We will monitor intestinal inflammation and tumor development by colonoscopy, weight loss and end point histology. These include the following:

• Dextran sodium sulfate (DSS-) colitis
• T cell transfer Colitis
• Citrobacter Rodentium infection
• Colitis associated colon cancer model
• Intestinal wounding using the endoscopy and a biopsy forceps.
• Endoscopic disease monitoring

Mouse models for autoimmune diseases

• EAE (Experimental autoimmune encephalomyelitis
• NTN /Nephrotoxic Nephritis)

16S rRNA sequence analysis:

One key component influencing the immune system in the intestine is the microbiota. We have established a collaboration with the group from Dr. Till Strowig from the Helmholtz Zentrum für Infektionsforschung in Braunschweig, who is performing these analyses with us.

Next Gene Seq: to deconvolute the transcriptional changes during the conversion of T helper cells toward alternative fates.

The usage of unbiased approaches is a key step in analysing complex systems. We have accumulated a lot of experience with the SMARTer Ultra Low RNA kit from Clontech. This kit allows us to sequence the transcriptome from a small number of cells (500). Furthermore, we have established in collaboration with Prof. Gagliani the DropSeq technique, which allows us to simultaneously profile the transcriptome of huge amounts of cells with single-cell resolution. The bioinformatics analysis is performed by Dr. Babett Steglich in my lab. Principle component analysis, heat map, hierarchical cluster analysis, volcano plot and several other analyses will be performed within the scope of the experiment.

CRISPR/Cas9: to analyse in vivo the role of the candidate genes identified by Next Gen Seq. Our aim is to test the role of candidate genes, identified by next gen sequencing analysis in vivo. With this technology, it is possible to generate multiple conditional knock out mouse lines and test the role of the candidate molecules and in turn disease susceptibility. This technique has been established in the last years in collaboration with Prof. Gagliani and Dr. Irm Hermans-Borgmeyer (transgenic mouse core facility of the UKE), who is also performing the injections into the cytoplasm of fertilized eggs.

Kempski J, Giannou AD, Riecken K, Zhao L, Steglich B, Lücke J, Garcia-Perez L, Karstens KF, Wöstemeier A, Nawrocki M, Pelczar P, Witkowski M, Nilsson S, Konczalla L, Shiri AM, Kempska J, Wahib R, Brockmann L, Huber P, Gnirck AC, Turner JE, Zazara DE, Arck PC, Stein A, Simon R, Daubmann A, Meiners J, Perez D, Strowig T, Koni P, Kruglov AA, Sauter G, Izbicki JR, Guse AH, Rösch T, Lohse AW, Flavell RA, Gagliani N*, Huber S*. IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans. Gastroenterology 2020;159:1417-30.e3.

Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A, Konczalla L, Brockmann L, Wahib R, Xu H, Vesely MCA, Soukou S, Steglich B, Bedke T, Manthey C, Seiz O, Diercks BP, Gnafakis S, Guse AH, Perez D, Izbicki JR, Gagliani N, Flavell RA*, Huber S*.TGF-beta signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat Commun 2020;11:2608.

Brockmann L, Soukou S, Steglich B, Czarnewski P, Zhao L, Wende S, Bedke T, Ergen C, Manthey C, Agalioti T, Geffken M, Seiz O, Parigi SM, Sorini C, Geginat J, Fujio K, Jacobs T, Roesch T, Izbicki JR, Lohse AW, Flavell RA, Krebs C, Gustafsson JA, Antonson P, Roncarolo MG, Villablanca EJ, Gagliani N*, Huber S*. Molecular and functional heterogeneity of IL-10-producing CD4(+) T cells. Nat Commun 2018;9:5457.

Pelczar P, Witkowski M, Perez LG, Kempski J, Hammel AG, Brockmann L, Kleinschmidt D, Wende S, Haueis C, Bedke T, Witkowski M, Krasemann S, Steurer S, Booth CJ, Busch P, König A, Rauch U, Benten D, Izbicki JR, Rösch T, Lohse AW, Strowig T, Gagliani N, Flavell RA*, Huber S*. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 2016;354:358-62.

Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S*, Flavell RA*. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015;523:221-5.

Gagliani N*, Magnani CF*, Huber S*, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 2013;19:739-46.

Huber S*, Gagliani N*, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O'Connor W Jr, Murphy AJ, Valenzuela DM, Yancopoulos GD, Booth CJ, Cho JH, Ouyang W, Abraham C, Flavell RA. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 2012;491:259-63.

Esplugues E*, Huber S*, Gagliani N, Hauser AE, Town T, Wan YY, O'Connor W Jr, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA. Control of TH17 cells occurs in the small intestine. Nature 2011;475:514-8.

Huber S*, Gagliani N*, Esplugues E*, O'Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA. Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011;34:554-65.

*equally contributing authors

Principal Investigator (PI)

Prof. Dr. med. Samuel Huber

Postdocs:

Dr. rer. nat. Tanja Bedke

Anastasios Giannou, MD, Ph.D.

Dr. med. Sina Hübener

Dr. med. Francis Huber

Dr. rer. nat. Penelope Pelczar

Babett Steglich, Ph.D. (auch AG Gagliani )

Andres Pablo Machicote, Ph.D.

Dr. rer. nat. Antonella Fazio

Lis Noelia Velasquez, Ph.D.

Dr. med. Can Ergen-Behr

Ph.D. - and MD-candidates:

Franziska Bertram, cand. med.

Marius Böttcher, MD

Jan Kempski, cand. med.

Mikolaj Nawrocki, cand. med.

Mustafa Shiri, M.Sc.

Friederike Stumme, M.Sc.

Beibei Liu, cand. med.

Rongrong Jia, cand. med.

Tao Zhang, cand. med.

Loreen Heuer, cand. med.

Lennart Bauditz, cand. med.

Anissa Franke, cand. med.

Philipa Loose, cand. med.

Technician:

Cathleen Haueis, BTA

Sandra Wende, BTA

Endogene Alarmsignale in Regulation von Immunantworten

Entzündliche Prozesse sind Bestandteil der komplexen immunologischen Antwort eines Organismus auf sterile oder infektiöse Schädigung vaskularisierter Gewebe. Während die entzündungsfördernden Funktionen von inflammatorischen Zytokinen und Chemokinen in vielen Geweben gut untersucht und belegt sind, bleibt ungeklärt, auf welche Weise geschädigte Zellen diese Signalkaskaden auslösen und wie die resultierenden Entzündungsreaktionen reguliert werden. Es wird angenommen, dass in prinzipiell jedem Organ gestresste oder zerfallende Zellen Bestandteile freisetzen können, die über spezifische, evolutionär konservierte Rezeptorsysteme entzündliche Kaskaden und regenerative Prozesse in Gang setzen. Diese zellulären Bestandteile werden als "damage-associated molecular patterns" (DAMPs) oder "Alarmine" bezeichnet. Im Gegensatz dazu gelten klassischerweise molekulare Bestandteile von Pathogenen (z.B. Lipopolysaccharid, LPS) als Auslöser infektassoziierter Entzündungen und werden dementsprechend als "pathogen-associated molecular patterns" (PAMPs) bezeichnet. Diese ursprünglich fast paradigmatische konzeptuelle Unterscheidung zwischen sterilen und infektiösen Entzündungsmechanismen weicht indes zunehmend einem Verständnis, in dem Parenchymzellen, Entzündungszellen und gegebenenfalls exogene Pathogene in ein komplexes Zusammenspiel dynamischer gegenseitiger Beeinflussung treten.

Wir haben gezeigt, dass das ubiquitär exprimierte körpereigene Alarmin High-mobility group box 1 (HMGB1) im Zusammenspiel mit seinem Hauptrezeptor RAGE essenziell für die Rekrutierung von Entzündungszellen nach steriler nekrotischer Gewebsschädigung ist, und dass diese Entzündungszellen aktiv zur Gewebsschädigung beitragen. Der evolutionäre Vorteil dieses Mechanismus könnte in einem "Präventivschlag" gegen mikrobielle Besiedelung von Wundflächen liegen, der um den Preis einer zunächst verstärkten Gewebsschädigung erkauft wird. Der Fokus unserer Arbeitsgruppe liegt daher auf der Rolle körpereigener Alarmsignale in der Initiation und Unterhaltung entzündlicher Prozesse im Rahmen von infektiösen Erkrankungen, die in sehr unterschiedlichem Ausmaß mit qualitativ und quantitativ heterogenen Zell- und Organschädigungen einhergehen. Neben der Aufklärung relevanter zellulärer Effektoren dieser endogenen Schiene der Immunaktivierung befassen wir uns mit der Frage, inwiefern körpereigene Botenstoffe als immunologisches Adjuvans in der Ausbildung einer adaptiven Immunantwort benötigt werden.

Mitarbeiter

Dr. Peter Hübener, Oberarzt

Elisabeth Zierz, M.Sc.

Irke Wassmann, M.Sc.

Ausgewählte Publikationen

Volmari A*, Foelsch K*, Zierz E1, Yan K, Qi M, Bartels K, Kondratowicz S, Boettcher M, Reimers D, Nishibori M, Liu K, Schwabe RF, Lohse AW, Huber S, Mittruecker HW, Huebener P. Leukocyte-derived High-mobility group box 1 governs hepatic immune responses against Listeria monocytogenes. Hepatology Communications 2021 doi: https://doi.org/10.1101/797902

Hoste E, Maueröder C, van Hove L, Catrysse L, Vikkula HK, Sze M, Maes B, Karjosukarso D, Martens L, Gonçalves A, Parthoens E, Roelandt R, Declercq W, Fuentes I, Palisson F, Gonzalez S, Salas-Alanis JC, Boon L, Huebener P, Mulder KW, Ravichandran K, Saeys Y, Schwabe RF, van Loo G. Epithelial HMGB1 Delays Skin Wound Healing and Drives Tumor Initiation by Priming Neutrophils for NET Formation. Cell Rep 2019;29:2689-2701.e4.

Hernandez C*, Huebener P*, Pradere JP, Antoine DJ, Friedman RA, Schwabe RF. HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis. J Clin Invest 2018;128:2436-51.

Kleinschmidt D, Giannou AD, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, Lohse AW, Axelrod J, Galun E, Flavell RA, Gagliani N, Huber S. A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury. J Immunol 2017;199:4078-90.

Hernandez C*, Hübener P*, Schwabe RF. Damage-associated molecular patterns in cancer a double-edged sword. Oncogene 2016;35:5931-41.

Karimi K, Keßler T, Thiele K, Ramisch K, Erhardt A, Hübener P, Barikbin R, Arck P, Tiegs G. Prenatal acetaminophen induces liver toxicity in dams, reduces fetal liver stem cells, and increases airway inflammation in adult offspring. J Hepatol 2015;62:1085-91.

Hübener P, Gwak GY, Schwabe RF. Comment on: HMGB1-dependent and -independent autophagy. Autophagy 2015;11:1187-88.

Hübener P*, Gwak GY*, Pradere JP, …, Goldberg IJ, Czaja MJ, Schwabe RF. High-mobility group box 1 is dispensable for autophagy, mitochondrial quality control, and organ function in vivo. CellMetab 2014;19:539-47.

Hübener P*, Pradere JP*, Hernandez C*, Gwak GY, Caviglia JM, Mu X, Loike JD, Jenkins RE, Antoine DJ, Schwabe RF. The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis. J Clin Invest 2015;125:539-50.

*equally contributing authors

General Information

In this lab we like studying the basic aspects of T cell biology, adaptation to environmental changes, and ultimately, how T cells either mediate physiological responses to pathogens or pathological tissue damaging processes. We combine different scientific methods and expertise to study the transcriptional and epigenetic regulation of key cytokine genes and the cellular trajectory and function of T cells in different non lymphoid tissues. We also make use of several mouse models of infections and diseases. Finally, we use system biology approaches and human samples to test the clinical relevance of our basic discoveries to provide the first step towards better therapies for human diseases.

Key technologies available in the lab:

• Conditional KO mouse models
• Cytokine reporter mouse models
• Fate mapping mouse models
• In vivo and in vitro Cas9
• Germ-free facility
• Single Cell RNA/TCR/CITE seq
• System biology in collaboration with Prof. S. Bonn

Principal Investigator (PI) - Prof. Nicola Gagliani Ph.D.

Contact profil - Prof. Nicola Gagliani Ph.D.
More information - Research Portal UKE

PostDocs:

Theodora Agalioti Ph.D.
Babett Steglich Ph.D. (part also of AG Prof. S. Huber)
Franzisca Muscate Ph.D.
Francesco Siracusa Ph.D.
Filippo Cortesi Ph.D.
Yogesh Kumar Ph.D.

Clinician Scientists:

Anna Wostemeier MD
Jenny Krause MD
Jonas Wagner MD
Joseph Tintelnot MD

Ph.D. students:
Yang Xu MD
Guido Rattay

Technicians:
Petra Market MTA
Ayob Aleko MTA

Management & Communication:
Dana Klatt

General information and list of ongoing projects

The AG Schulze zur Wiesch aims to understand the immunological control and immunopathology of different chronic viral diseases like viral hepatitis and HIV. The focus of our translational investigations is the exact understanding and characterization of the virus-specific T cell response of these diseases and of individual patients (“from bed to bench”). The group consists of both biologists and PhD students as well as MDs and MD students. Funding is provided by a broad range of organizations (DFG SFB841+SFB1328), German Center for Infection (DZIF), EU and AmfAR, altogether reflecting the breadth of the different topics and diseases studied in this group in a collaborative way.

We are employing a number of different state of the art methods like multicolor flow cytometry, intracellular cytokine staining, MHC class I +II tetramer staining, ELISpot-assays, PCR and cell cultures to understand the molecular mechanisms of viral chronicity in patient blood and tissue samples (eg. liver biopsies and intestinal mucosa). Overall, we see that the virus-specific immune response is blunted in many cases by expression of co-inhibitory molecules and pathways in patients with chronic disease and are trying to find novel avenues to re-invigorate the antiviral immune response.

As translational immunological group we take part in several clinical vaccine and immune interventional studies.

List of ongoing research projects:

Autoimmunology-related projects:

• The role of ectonucleotidases in patients with Graft-versus-Host disease (GvHD) and inflammatory bowel disease (IBD)
  

HIV-related projects:HIV-related projects:

• Icistem project
• European HIV vaccine alliance
• Studies of the viral reservoir in HIV infection / finding the needle in the haystack
• Shock and kill strategy to eliminate latently infected cells
• Gammadelta Regulatory T cells in HIV Infection
  

• Ex vivo characterization of coinhibitory molecules on MHC class II tetramer positive HCV-specific T cells in HCV infection
  

• Specific T cells in Malaria
  

General Information

In our lab, we study the interaction among cancer, stroma and immune cells with the long-term aim of enabling future therapies to prevent or treat metastasis formation. Our team has expertise on cancer and related metastasis. By using transgenic mice combined with metastasis models and state-of-the art microsurgical techniques (e.g., trachea, lung, liver and intestine transplantation in mouse and rat models) we aim to understand how target metastasis organ microenvironment can be modulated to prevent or treat metastasis and to study complex cellular mechanisms directly in vivo, such as the emergence and function of tissue-resident immune cells. Finally, we use human samples isolated from patients suffering from metastasis in order to be able to translate our findings into the human condition.

Key methods-technologies available in the lab:

• Conditional Knock out mouse models
• Culture of colon organoids carrying specific mutations
• Forced models of liver and lung metastasis
• Spontaneous models of liver and lung metastasis
• Organ Transplantation (Orthotopic single left lung, liver, trachea and small intestine transplantation)
• Models of liver and lung carcinogenesis
• In vitro and in vivo transmigration assays of cancer cells
• Extravasation assays
• Isolation of lung and live endothelial cells and in vitro and in vivo endothelial assays
• Germ-free facility
• Single Cell RNA seq

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Figure 1. Graphical abstract summarizing the role of iNKT17 cell-derived IL-22 in regulating vascular endothelium and thereby promoting cancer cell extravasation and liver metastasis formation. Tissue resident iNKT17 cell derived IL-22 is promoting the early extravasation of CRC cancer cells into the liver parenchyma by increasing the permeability of the endothelium via ANPEP (Giannou et al., Immunity, 2023).

Selected publications

Giannou AD#, Kempski J#, Shiri AM#, Lücke J, Zhang T, Zhao L, Zazara DE, Cortesi F, Riecken K, Amezcua Vesely MC, Low JS, Xu H, Kaffe E, Garcia-Perez L, Agalioti T, Yamada Y, Jungraithmayr W, Zigmond E, Karstens KF, Steglich B, Wagner J, Konczalla L, Carambia A, Schulze K, von Felden J, May P, Briukhovetska D, Bedke T, Brockmann L, Starzonek S, Lange T, Koch C, Riethdorf S, Pelczar P, Böttcher M, Sabihi M, Huber FJ, Reeh M, Grass JK, Wahib R, Seese H, Stüben BO, Fard-Aghaie M, Duprée A, Scognamiglio P, Plitzko G, Meiners J, Soukou S, Wittek A, Manthey C, Maroulis IC, Arck PC, Perez D, Gao B, Zarogiannis SG, Strowig T, Pasqualini R, Arap W, Gosálvez JS, Kobold S, Prinz I, Guse AH, Tachezy M, Ghadban T, Heumann A, Li J, Melling N, Mann O, Izbicki JR, Pantel K, Schumacher U, Lohse AW, Flavell RA, Gagliani N, Huber S. Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22. Immunity 2023;56:125-142.e12. doi:10.1016/ j.immuni.2022.12.014.

Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, Pelczar P, Kylies D, Puelles VG, Bielecka AA, Peschka M, Cortesi F, Riecken K, Jung M, Amend L, Bröring TS, Trajkovic-Arsic M, Siveke JT, Renné T, Zhang D, Boeck S, Strowig T, Uzunoglu FG, Güngör C, Stein A, Izbicki JR, Bokemeyer C, Sinn M, Kimmelman AC, Huber S#, Gagliani N#. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 2023; Mar;615(7950):168-174. doi: 10.1038/s41586-023-05728-y. Epub 2023 Feb 22.

Giannou AD#, Kempski J#, Zhang T#, Lücke J#, Shiri AM, Zazara DE, Belios I, Machicote A, Seeger P, Agalioti T, Tintelnot J, Sagebiel A, Tomczak M, Bauditz L, Bedke T, Kocheise L, Mercanoglu B, Fard-Aghaie M, Giorgakis E, Lykoudis PM, Pikouli A, Grass JK, Wahib R, Bardenhagen J, Brunswig B, Heumann A, Ghadban T, Duprée A, Tachezy M, Melling N, Arck PC, Stringa P, Gentilini MV, Gondolesi GE, Nakano R, Thomson AW, Perez D, Li J, Mann O, Izbicki JR, Gagliani N, Maroulis IC#, Huber S#. IL-22BP controls the progression of liver metastasis in colorectal cancer. Front Oncol 2023; May 31;13:1170502. doi: 10.3389/fonc.2023.1170502. eCollection 2023.

Lücke J#, Nawrocki M#, Schnell J, Meins N, Heinrich F, Zhang T, Bertram F, Sabihi M, Böttcher M, Blankenburg T, Pfaff M, Notz S, Kempski J, Reeh M, Wolter S, Mann O, Izbicki JR, Lütgehetmann M, Duprée A, Giannou AD#, Ondruschka B#, Huber S#. TNFα aggravates detrimental effects of SARS-CoV-2 infection in the liver. Front Immunol 2023; Mar 31;14:1151937. doi: 10.3389/fimmu.2023.1151937. eCollection 2023.

Zhao L#, Giannou AD#, Xu Y#, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L#, Huber S#, Gagliani N#. Efferocytosis fuels malignant pleural effusion through TIMP1. Sci Adv 2021;7:eabd6734. doi:10.1126/sciadv.abd6734.

Zhao L#, Giannou AD#, Xu Y#, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L#, Huber S#, Gagliani N#. Efferocytosis fuels malignant pleural effusion through TIMP1. Sci Adv 2021;7:eabd6734. doi:10.1126/sciadv.abd6734.

Kempski J#, Giannou AD#, Riecken K, Zhao L, Steglich B, Lücke J, Garcia-Perez L, Karstens KF, Wöstemeier A, Nawrocki M, Pelczar P, Witkowski M, Nilsson S, Konczalla L, Shiri AM, Kempska J, Wahib R, Brockmann L, Huber P, Gnirck AC, Turner JE, Zazara DE, Arck PC, Stein A, Simon R, Daubmann A, Meiners J, Perez D, Strowig T, Koni P, Kruglov AA, Sauter G, Izbicki JR, Guse AH, Roesch T, Lohse AW, Flavell RA, Gagliani N#, Huber S#. IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans. Gastroenterology 2020;159:1417-30. doi:10.1053/j.gastro.2020.06.033. Epub 2020 Jun 22.

Kanellakis NI#, Giannou AD#, Pepe MAA#, Agalioti T, Zazara DE, Giopanou I, Psallidas I, Spella M, Marazioti A, Arendt KAM, Lamort AS, Champeris Tsaniras S, Taraviras S, Papadaki H, Lilis I#, Stathopoulos GT#. Tobacco chemical-induced mouse lung adenocarcinoma cell lines pin the prolactin orthologue proliferin as a lung tumour promoter. Carcinogenesis 2019;Nov 25;40(11):1352-1362. doi:10.1093/carcin/bgz047.

Kleinschmidt D#, Giannou AD#, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, Lohse AW, Axelrod JH, Galun E, Flavell RA, Gagliani N, Huber S. A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury. J Immunol 2017;199:4078-90. doi:10.4049/jimmunol.1700587. Epub 2017 Nov 6.

Agalioti T#, Giannou AD#, Krontira AC#, Kanellakis NI, Kati D, Vreka M, Pepe M, Spella M, Lilis I, Zazara DE, Nikolouli E, Spiropoulou N, Papadakis A, Papadia K, Voulgaridis A, Harokopos V, Stamou P, Meiners S, Eickelberg O, Snyder LA, Antimisiaris SG, Kardamakis D, Psallidas I, Marazioti A, Stathopoulos GT. Mutant KRAS promotes malignant pleural effusion formation. Nat Commun 2017;8:15205. doi:10.1038/ncomms15205.

Giannou AD#, Marazioti A#, Kanellakis NI#, Giopanou I#, Lilis I, Zazara DE, Ntaliarda G, Kati D, Armenis V, Giotopoulou GA, Krontira AC, Lianou M, Agalioti T, Vreka M, Papageorgopoulou M, Fouzas S, Kardamakis D, Psallidas I, Spella M#, Stathopoulos GT#. NRAS destines tumor cells to the lungs. EMBO Mol Med 2017;9:672-86. doi:10.15252/emmm.201606978.

Giannou AD, Marazioti A, Spella M, Kanellakis NI, Apostolopoulou H, Psallidas I, Prijovich ZM, Vreka M, Zazara DE, Lilis I, Papaleonidopoulos V, Kairi CA, Patmanidi AL, Giopanou I, Spiropoulou N, Harokopos V, Aidinis V, Spyratos D, Teliousi S, Papadaki H, Taraviras S, Snyder LA, Eickelberg O, Kardamakis D, Iwakura Y, Feyerabend TB, Rodewald HR, Kalomenidis I, Blackwell TS, Agalioti T, Stathopoulos GT. Mast cells mediate malignant pleural effusion formation. J Clin Invest. 2015 Jun;125(6):2317-34. doi: 10.1172/JCI79840. Epub 2015 Apr 27.

#equally contributing authors

Principal Investigator

Anastasios Giannou, NP, MD, MSc, PhD.

PostDoc

• Tao Zhang, MD

Clinician Scientists

• Jöran Lücke
• Philipp Seeger

PhD students

• Siwen Zhang
• Eleftherios Papazoglou

MD students

• Lennart Bauditz, cand. med.

Technician

• Tom Blankenburg, MTA

• 
• 

Funding

Anastasios Giannou is funded by: Deutsche Krebshilfe, DFG (RU 5068), Erich und Gertrud Roggenbuck-Stiftung, Else Kröner Fresenius Stiftung, Fritz Thyssen Stiftung, German Academic Exchange Service (DAAD), Hamburger Krebsgesellschaft e.V., JUNG-Stiftung, Monika Kutzner Stiftung, UKE, Werner-Otto-Stiftung (alphabethical order).

General information

Our laboratory focuses on studying the mechanisms that regulate macrophage responses during infections or in response to sterile damage. Specifically, our work centers on dissecting the impact of phagocytosis of dying cells, a key function carried out by macrophages in every tissue of our body, on their capacity to trigger tissue remodeling. Our data indeed indicate that phagocytosis of dying cells by macrophages is not merely a cleaning process but significantly influences macrophage behavior. Based on these findings, we are examining tissue-specific factors contributing to the transcriptional and functional heterogeneity of phagocytic macrophages in various contexts, including homeostasis, infection with the parasite Schistosoma mansoni, and in murine models of colitis, inflammation-driven cancer, autoimmune liver diseases and upon metabolic challenges. In all of these scenarios, we have access to human tissues to implement our discoveries, thanks to our affiliation with the I. Department of Medicine at the UKE and our guest associate position at the Bernhard Notch Institute for Tropical Medicine.

By delving deep into the mechanisms of how macrophages engage in phagocytosis and the resulting implications on tissue homeostasis, immune responses, and disease progression, we aim to contribute to the development of innovative strategies that can improve the treatment and management of various diseases.

List of ongoing research projects

• The impact of apoptotic cell nature on macrophage function
• Phagocytic macrophage control of cholangitis progression
• The paradoxical role of IL-23 released by phagocytic macrophages in the damaged liver
• Dying cell-derived extracellular vesicles and their impact on macrophage behavior
• Lipid processing and phagocytic capacity of adipose tissue macrophages

Selected Publications

Staufer T, Körnig C, Liu B, Liu Y, Lanzloth C, Schmutzler O, Bedke T, Machicote A, Parak WJ, Feliu N, Bosurgi L, Huber S, Grüner F. Enabling X-ray fluorescence imaging for in vivo immune cell tracking. Sci Rep 2023 Jul 17;13(1):11505.

Dörk R, Pelczar P, Shiri AM, Volmari A, Zierz E, Giannou A, Böttcher M, Bosurgi L, Huber S, Manthey CF. Myeloid cell specific deletion of PDGFR-α promotes dysbiotic intestinal microbiota and thus increased colitis susceptibility. J Crohns Colitis 2023 Jun 28;jjad103.

Liebold I, Meyer S, Heine M, Kuhl A, Witt J, Eissing L, Fischer AW, Koop AC, Kluwe J, Wiesch JSZ, Wehmeyer M, Knippschild U, Scheja L, Heeren J, Bosurgi L#, Worthmann A#. TREM2 Regulates the Removal of Apoptotic Cells and Inflammatory Processes during the Progression of NAFLD. Cells. 2023 Jan 17;12(3):341.

Zhao L*, Giannou AD*, Xu Y*, Shiri AM, Liebold I, Steglich B, Bedke T, Zhang T, Lücke J, Scognamiglio P, Kempski J, Woestemeier A, Chen J, Agalioti T, Zazara DE, Lindner D, Janning M, Hennigs JK, Jagirdar RM, Kotsiou OS, Zarogiannis SG, Kobayashi Y, Izbicki JR, Ghosh S, Rothlin CV, Bosurgi L#, Huber S#, Gagliani N#. Efferocytosis fuels malignant pleural effusion through TIMP1. Sci Adv. 2021 Aug 13; 7(33):eabd6734.

Liebold I, Jawazneh AA, Hamley M, Bosurgi L. Apoptotic cell signals and heterogeneity in macrophage function: Fine-tuning for a healthy liver. Semin Cell Dev Biol. 2021 Nov;119:72-81.

Zhao Y*, Kilian C*, Turner JE*, Bosurgi L*, Roedl K*, Bartsch P, Gnirck AC, Cortesi F, Schultheiß C, Hellmig M, Enk LUB, Hausmann F, Borchers A, Wong MN, Paust HJ, Siracusa F, Scheibel N, Herrmann M, Rosati E, Bacher P, Kylies D, Jarczak D, Lütgehetmann M, Pfefferle S, Steurer S, Zur-Wiesch JS, Puelles VG, Sperhake JP, Addo MM, Lohse AW, Binder M, Huber S, Huber TB, Kluge S, Bonn S, Panzer U, Gagliani N#, Krebs CF#. Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients. Sci Immunol 2021; 6:eabf6692.

de Freitas E Silva R, Gálvez RI, Pereira VRA, de Brito MEF, Choy SL, Lotter H, Bosurgi L, Jacobs T. Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4 + T Effector and Regulatory T Cells in Cutaneous Leishmaniasis. Front Immunol. 2020 Oct 22; 11:574491.

Bosurgi L*, Hughes LD*, Rothlin CV, Ghosh S. Death begets a new beginning. Immunol Rev. 2017 Nov;280(1):8-25.

Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, Gagliani N, Craft JE, Flavell RA, Ghosh S, Rothlin CV. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017; 356(6342):1072-1076.

Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, Dixit VD. IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Rep. 2017 Apr 11;19(2):225-234.

*equally contributing authors

Principal Investigator

Lidia Bosurgi, PhD

PostDoc

Dr. rer. nat. Imke Liebold

PhD students

• Stephanie Leyk, Ph.D. candidate
• Simon Meyer, Ph.D. candidate
• Clarissa Lanzloth, Ph.D. candidate

Previous lab members

• Dr. rer. nat. Madeleine Hamley
• Dr. rer. nat. Amirah Al Jawazneh
• Dr. med. Felix Piecha, Clinician Scientist
• Benjamin Kruft, MSc

Virushepatitis

Häufigster und wichtigster Auslöser einer Leberschädigung sind Infektionserreger, wobei Hepatitisviren eine zentrale Rolle spielen. Weltweit sind fast 500 Millionen Menschen chronisch mit Hepatitis-B-, D- und C-Viren infiziert. Langfristig führt dies zu einem erhöhten Risiko, an Lebezirrhose und an einem hepatozellulären Karzinom zu erkranken. Das Forschungsfeld der viralen Hepatitis wurde durch das Fehlen geeigneter Zellkultursysteme und Tiermodelle stark limitiert. Unsere Arbeitsgruppe benutzt ein einzigartiges Transplantationsmodell, das auf der Repopulierung der Mausleber mit fremden Hepatozyten basiert. Als Empfängertiere dienen Mäuse, bei denen aufgrund eines leberzell-toxisch wirkenden Transgens (uPA: Uroplasminogenaktivator) endogene Maushepatozyten zu Grunde gehen. Dies ermöglicht eine fast komplette Rekonstitution der Mausleber mit menschlichen Leberzellen. Das dauerhafte Überleben der transplantierten Fremd-Hepatozyten wird durch das Einkreuzen immundefizienter Mäusen (SCID/beige oder SCID/IL2γr) erreicht, sodass keine Abstoßungsreaktionen stattfinden können. Diese "humanisierten" Mäuse können nun mit humanen Hepatitisviren (HBV, HDV, HCV und HEV) infiziert werden (Fig.1), worauf es zu einer persistierenden Virämie kommt, die der natürlichen viralen Infektion beim Menschen vergleichbar ist. Durch die Nutzung dieses Modells können wir erstmalig den kompletten Replikationszyklus dieser Viren in vivo untersuchen, sowie die Wirksamkeit verschiedener, sich in der Entwicklung befindlicher antiviraler Medikamente testen.

Forschungsschwerpunkt

• Präklinische Studien um verbesserte Behandlungsmethoden zu entwickeln (Testung neuer Medikamente)
• Molekulare Mechanismen der HBV- und HDV-Persistenz
• Interaktionen zwischen humanen hepatotropen Viren (HBV, HDV, HCV, HEV) und der humanen angeborenen Immunantwort (das heißt Interferon-Signalwege)

Themenbereich HBV (Projektleiterin: Prof. Dr. Maura Dandri)

Die bisherigen Heilungsraten durch antivirale Therapie mit Inhibitoren der HBV-Replikation (Nukleosidanaloga) oder mit Interferon sind leider gering. Ursächlich ist die fehlende direkte therapeutische Beeinflussbarkeit der im Zellkern von Hepatozyten vorliegenden Form des HBV-Virus, der sog. "covalently closed circular" DNA (cccDNA). Die cccDNA spielt eine zentrale Rolle im HBV-Replikationszyklus, indem sie als ständige Matrize zur Replikation neuer Viruspartikel dient. Mithilfe dieses Maussystems können nun neue antivirale Substanzen getestet werden. So wurde in Zusammenarbeit mit Prof. S. Urban (Heidelberg) der therapeutische Effekt einer Eintrittsblockade auf die HBV-Infektion untersucht und gezeigt, dass der Eintrittshemmer Myrcludex-B in der Lage ist, auch während einer bereits erfolgten Infektion die weitere Ausbreitung der Viren zu blockieren (Volz, J. Hepatology 2013). Das Projekt "Entry inhibition as a novel antiviral concept for hepatotropic viruses" wird vom BMBF (DZIF TTU-Hepatitis 05.804) gefördert. Die präklinische Testung neuerer antiviraler Substanzen in "humanisierten" Mäusen wird auch durch Kooperationen mit internationalen Institutionen und mit der Industrie durchgeführt.

Im Rahmen des SFB841 (A5: Molecular mechanisms of HBV persistence in chronically infected uPA chimeric mice) untersuchen wir die molekularen Mechanismen der HBV-Persistenz. Insbesondere gehen wir der Frage nach, wodurch die Aktivität der HBV-Matrize, das cccDNA-Molekül, modifiziert wird und welche Rolle die intrahepatische angeborene Immunantwort spielt. Mithilfe innovativer molekularer Methoden und in Zusammenarbeit mit Prof. M. Levrero (Univ. Rome) und Prof. U. Protzer (München) konnten wir zeigen, wie bestimmte Faktoren und therapeutische Zytokine (z.B. IFNα) die Aktivität (Belloni et al.J. Clin.Invest. 2012; Allweiss et al. J. Hepatology 2014) und die Stabilität (Lucifora et al. Science 2014) des viralen cccDNA Minichromosoms beeinflussen können. Beides hat zur Folge, dass die DNA teilweise stillgelegt oder sogar degradiert wird. Um die Interaktionen zwischen angeborener und adaptiver Immunantwort zu untersuchen, sollen uPA Mäuse auch partiell mit humanen Immunzellen rekonstituiert werden. Wir sind fest überzeugt, dass ein besseres Verständnis der HBV-Wirts-Interaktionen die Entwicklung wesentlich effektiverer Therapien ermöglich wird.

Themenbereich HDV (Projektleiter/in: Dr. Marc Lütgehetmann und Prof. Dr. Maura Dandri)

Von den 300 Millionen Menschen, die weltweit chronisch mit HBV infiziert sind, haben circa 5% ebenfalls eine Infektion mit dem Hepatitis-D-Virus (HDV). Weil HDV nur mit Hilfe des HBV-Oberflächenproteins die infizierten Zellen verlassen kann, kann es sich auch nur in Verbindung mit einer HBV-Infektion vermehren. Im chronischen Stadium einer HBV/HDV-Koinfektion zeigen die Betroffenen einen Krankheitsverlauf, der im Vergleich zu einer alleinigen HBV-Infektion schneller zur Leberzirrhose führen kann. Wir konnten zeigen, dass die chimären Lebern der HBV-infizierten Mäuse auch mit HDV superinfiziert oder ko-infiziert werden können (Lütgehetmann, Hepatology 2012). im Rahme des SFB841 (A8: Hepatitis-D-Virus-induzierte Pathogenese und Interaktion mit dem angeborenen Immunsystem) untersuchen wir Interaktionen zwischen HBV und HDV und dem humanen angeborenen Immunsystem sowie die virus-induzierte Pathogenese im Laufe einer Infektion mit HDV in humanisierten uPA-Mäusen.

Projektleiterin: Prof. Dr. rer. nat. Maura Dandri

Dr. med. Marc Lütgehetmann

Dr. rer. nat. Tassilo Volz

Dr. rer. nat. Lena Allweiss

Dr. rer. nat. Katja Giersch

Dr. rer. nat. Janine Kah

Dr. med. Jan-Hendrik Bockmann

Oliver Daniel Bhadra, Medizin Student, Grad. Kolleg (GRK841)

Sebastian Luft, Medizin Student, Grad. Kolleg (GRK841)

Aktuelle Kooperationen mit anderen Institutionen/Hochschulen

1) Prof. Dr. Stephan Urban, Department of Infectious Diseases, Molecular Virology, Universitätsklinikum Heidelberg

2) Prof. Dr. Ulrike Protzer, Institute of Virology,Technische Universität München / Helmholtz Zentrum München

3) Prof. Dr. med. Jörg Petersen, IFI Institut für interdisziplinäre Medizin an der Asklepiosklinik St. Georg, Hamburg

4) PD Dr. Jörg-Matthias Pollok, Chirurgisches Zentrum, Universitätsklinikum Bonn

5) PD Dr. Dieter Glebe, Institut für Medizinische Virologie, Justus-Liebig-Universität Gießen

6) Prof. Antonio Bertoletti, Emerging Infectious Diseases Duke-Nus Graduate Medical School, Singapore Institute for Clinical Sciences (A*Star), Singapore

7) Prof. Dr. Teresa Pollicino, Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy

8) Prof. Dr. Massimo Levrero, Department of Internal Medicine - DMISM, Laboratory of Gene Expression, La Sapienza University, Rome, Italy

9) Prof. Dr. John Murray, School of Mathematics and Statistics, Sydney University, Australien

10) Prof. Dr. Maria Buti, Hepatitis Laboratory, Biochemistry Department Vall d'Hebron Hospital, Barcelona, Spain

11) Prof. Camille Sureau, Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine (INTS), Paris, France12.

12) Prof. Dr. Thomas Baumert, Institut National de la Santé et de la Recherche Médicale, Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.

Publikationen

1. Giersch K, Allweiss L, Volz T, Helbig M, Bierwolf J, Lohse AW, Pollok JM, Petersen J, Dandri M, Lütgehetmann M. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J Hepatol 2015 Mar 17 doi: 10.1016/j.jhep.2015.03.011. [Epub ahead of print]

2. Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FH, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF. Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol 2015 Mar 23. doi: 10.1038/nbt.3179. [Epub ahead of print]

3. Oehler N, Volz T, Bhadra OD, Kah J, Allweiss L, Giersch K, Bierwolf J, Riecken K, Pollok JM, Lohse AW, Fehse B, Petersen J, Urban S, Lütgehetmann M, Heeren J, Dandri M. Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism. Hepatology 2014 Nov;60(5):1483-93

4. Allweiss L, Volz T, Lütgehetmann M, Giersch K, Bornscheuer T, Lohse AW, Petersen J, Ma H, Klumpp K, Fletcher SP, Dandri M. Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration. J Hepatol 2014 Mar 60(3):500-7.

5. Giersch K, Helbig M, Volz T, Allweiss L, Mancke LV, Lohse AW, Polywka S, Pollok JM, Petersen J, Taylor J, Dandri M, Lütgehetmann M. Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. J Hepatol 2014 Mar; 60(3):538-44.

6. Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF, Koppensteiner H, Makowska Z, Volz T, Remouchamps C, Chou WM, Thasler WE, Hüser N, Durantel D, Liang TJ, Münk C, Heim MH, Browning JL, Dejardin E, Dandri M, Schindler M, Heikenwalder M, Protzer U. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA Science. 2014 Mar 14;343(6176):1221-8.

7. Volz T, Allweiss L, M Barek MB, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol. 2013; 58: 861-7.

8. Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo G, Dandri M, Levrero M. IFNα inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 2012 Feb 1;122(2):529-37

9. Lütgehetmann M, Mancke LV, Volz T, Helbig M, Allweiss L, Bornscheuer T, Pollok JM, Lohse AW, Petersen J, Urban S, Dandri M. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 2012 Mar;55(3):685-94.

10. Lütgehetmann M, Bornscheuer T, Volz T, Allweiss L, Bockmann JH, Pollok JM, Lohse AW, Petersen J, Dandri M. Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon alpha in Chimeric Mice. Gastroenterology. 2011 Jun;140(7):2074-83.

Fall-Kontroll-Studie zu respiratorischen Erregern

Respiratorische Infektionen gehören weltweit zu den häufigsten Ursachen für eine fieberhafte Erkrankung bei Kindern, insbesondere auch im tropischen Afrika. Aktuell wird zur Diagnostik bei schweren respiratorischen Erkrankungen, bei vorhandenen Möglichkeiten, meist eine Multiplex-PCR auf bis zu 15 verschiedene Erreger durchgeführt. Da entsprechende Erreger häufig auch bei Gesunden nachgewiesen werden können, ist die Bedeutung einer positiven Reaktion in diesen Untersuchungen häufig unklar.

Um diese Frage zu klären, führen wir aktuell eine Fall-Kontroll-Studie in einem Krankenhaus in Ghana durch, bei der sowohl von Kindern, die sich wegen eines Atemwegsinfekts in stationärer Behandlung befinden, als auch von Kindern einer gesunden Kontrollgruppe Abstriche des Nasenrachenraumes angefertigt und diese auf insgesamt 20 mögliche bakterielle und virale Erreger untersucht werden. Durch den Vergleich der Prävalenz zwischen den Gruppen wird dann eine Aussage zur klinischen Relevanz der Erreger ermöglicht.

Untersuchung der nosokomialen Transmission von Multiresistenten Gram-negativen Erregern

Die weltweit zunehmende Bedeutung von multiresistenten bakteriellen Erregern ist unbestritten. Neben MRSA haben in den letzten Jahren gerade Resistenzen bei gram-negativen Erregern im Darm deutlich zugenommen, allerdings ist die Datenlage zur Prävalenz von Resistenzen in West Afrika sehr dürftig. Studien bei Reisenden zeigen eine vermehrte Akquisition von multiresistenten Erregern bei Reisen nach Asien und Afrika und Daten aus einer früheren Studie bei Kindern in Agogo (Ghana) zeigen eine Prävalenz von bis zu 80% extended spectrum beta lactamase (ESBL) produzierende Klebsiellen in
Blutkulturen.

Daher führen wir zur Zeit eine Studie in einem ghanaischen Krankenhaus durch, in der wir die Prävalenz und nosokomiale Transmission der Besiedelung mit ESBL- und Carbapenemase-produzierenden Bakterien untersuchen.

Publikationen

Association Between Malaria and Invasive non-typhoid Salmonella Infection in a Hospital Study – Accounting for Berkson’s Bias. Krumkamp , Kreuels B, Sarpong N, Gyau K, Foli G, Hogan B, Jaeger A, Reigl L, Zeeb H, Marks F, Adu-Sarkodie Y, May J. Clin Infect Dis 2015, In Press

A case of severe Ebola virus infection complicated by gram-negative septicemia. Kreuels B, Wichmann D, Emmerich P, Schmidt-Chanasit J, de Heer G, Kluge S, Sow A, Renné T, Günther S, Lohse AW, Addo MM, Schmiedel S. N Engl J Med. 2014

The causal effect of malaria on stunting: a Mendelian randomization and matching approach. Kang H*, Kreuels B*, Adjei O, Krumkamp R, May J, Small DS. Int J Epidemiol. 2013 *Equally contributed