Immunology, Infectious Diseases and Transplantation

The immune system has developed various mechanisms for responding to many pathogens, such as viruses and bacteria, and preventing disease and persistence of the pathogen in the infected host organism. However, many pathogens have also developed their own mechanisms to evade immune defence. Within this research programme, several groups study the molecular and cellular interactions of pathogens with the immune system in an effort to understand the fundamental mechanisms behind these interactions and from them develop new strategies for immunotherapy or vaccination. In Transplantation, the focus is on immunogenetic research and diagnostics, with the aim of understanding how the immune response is triggered, preventing rejections, and optimising donor and recipient matching. Several groups are also studying lymphozyte differentiation. The participating groups take both scientific and clinical approaches in their work. Immunology and Infectious Diseases belong to the five main research interests of the Medical Faculty of the UDE, which has positioned itself internationally and throughout Germany as a strong centre for infection research.

Helicobacter pylori colonises the human gastric epithelium as a result of specific adhesinreceptor interactions and is the main cause of stomach ulcers and stomach cancer. A research group led by PD Dr. Bernhard B. Singer (Institute of Anatomy) and colleagues from the Technical University of Munich have now discovered an entirely novel approach to the prevention or therapy of Helicobacter pylori infection and the diseases resulting from it. The findings indicate that interaction between the carcinoembryonic antigen family (CEACAMs) and the bacterial surface molecule HopQ can be used in diagnosis and therapy and may be a potentially promising new therapeutic target in combating diseases associated with H. pylori.

The Westendorf (Institute of Medical Microbiology) and Epple (Institute of Inorganic Chemistry) research groups have developed a new and promising strategy for treating chronic inflammatory bowel disease locally and with few side effects. Using calcium phosphate and polylactic-co-glycolic acid nanoparticles, which are not harmful to the human body, the researchers succeeded in stabilising the generally unstable siRNA and introducing it gently into the inflamed large intestine. There it is able to disarm inflammatory cytokines TNF-alpha, IP-10 and KC, which are involved in the development of chronic inflammatory bowel diseases. In a mouse model the scientists demonstrated that the epithelium cells and immune cells of the intestine take up the siRNA nanoparticles locally and significantly suppress the work of the target genes.

If patients with an impaired immune system additionally contract a fungal infection (Aspergillosis), it is vital that they receive early treatment with a therapy that is suited to their specific needs. Researchers in the EU consortium “MATHIAS” (New Molecular-Functional Imaging Technologies and Therapeutic Strategies for Theranostic of Invasive Aspergillosis), with significant contributions from the team of Prof. Matthias Gunzer (Institute of Experimental Immunology and Imaging), have developed a new and promising diagnostic procedure and successfully tested it in a clinical study. It uses an imaging technique that combines positron emission tomography (PET) with magnetic resonance imaging (MRI). The disease is made visible with the aid of radioactively marked antibodies, which only attach to certain structures on the growing fungus. The antibody-based imaging makes it possible in the process to rule out that any unusual structures in the lung are attributable to bacterial or viral infections. The resulting fast and reliable diagnosis may be an alternative to the painful, and in some cases dangerous, diagnostic method used to date.

At the end of 2016, the first institute for HIV research in Germany was opened in the Faculty of Medicine at UK Essen. The scientific director is Prof. Hendrik Streeck, a leading international expert for the fatal immune deficiency disease. The new institute’s long-term goal is to develop a HIV vaccine. This is planned to take place on a national level, through the nationwide network of vaccine researchers, and internationally. The UDE scientists are therefore collaborating closely with partners in the USA, Africa and Thailand to develop novel vaccines and test them in the early stages of their development. Other cooperation for combining expert resources and creating synergies exists with the German AIDS Foundation and the Schreiter Foundation and is supported by the Bonn Opera Gala’s work for the German AIDS Foundation. In the search for a HIV vaccine, the Streeck research group was able to identify a small population of endogenous T follicular helper (Tfh) cells in blood. These cells, which are normally only found in the lymph nodes, specifically detect HI viruses and can release corresponding messenger substances. The cells play a significant role in triggering signals of protective antibody responses and in this way build up protection against the virus. Understanding and being able to control these signals will make it possible to develop targeted vaccines.

Selected current research projects:

How viruses are able to survive in the host body and avoid the defences of its immune system is the subject of research by scientists from Duisburg-Essen, Wuhan, Bochum and Shanghai in the Collaborative Research Centre Transregio 60 SFB/TRR 60 “Mutual interaction of chronic viruses with cells of the immune system: from fundamental research to immunotherapy and vaccination”. The common goal of all the participating institutes from Medicine, Biology and Chemistry is to develop drugs and vaccines that are able to overcome the “braking mechanisms” of the immune system and thereby end virus infections. The German-Chinese collaboration was consolidated in 2017 when the Wuhan-Essen Joint Lab of Infection and Immunity was established.

(Junior) researchers from different areas of infectious diseases and immunology are working together in the DFG-funded Research Training Group (GRK) 1949 “Immune Response in Infectious Diseases – Regulation between Innate and Adaptive Immunity”. Coordinated by Prof. Astrid Westendorf, the group is exploring the question of how congenital and acquired immune response influence each other.

The focus of interest in GRK 2098 “Biomedicine of the acid sphingomyelin/acid ceramide system”, led by Prof. Erich Gulbins (Institute of Molecular Biology), is on sphingolipids, important components of the cell membrane from the lipids class of compounds. Recent research findings have shown that they play a significant functional role in many cellular processes. The doctoral projects are focused on the acid sphingomyelinase (Asm)/ceramide/acid ceramidase (Ac)/sphingosine/ sphingosine kinase (SPK)/sphingosine 1-phosphate (S1P) pathway and investigate its importance in inflammatory disorders, infectious diseases, cancer or cardiovascular disease. All the projects translate the basic research into clinical applications through preclinical projects.

Alongside the Research Training Group, a DFG Research Unit funded since 2014 is also concerned with the function of sphingolipids. In FOR 2123 “Sphingolipid dynamics in infection control”, the groups led by Prof. Erich Gulbins (deputy coordinator) and Dr. Heike Grassmé (Institute of Molecular Biology) are working with scientists in Würzburg and Potsdam to study the role of sphingolipids during infection of host cells by pathogens, especially bacteria. The DFG extended FOR 2123 with effect from 1 July 2017. Work includes projects in the area of analysis of molecular mechanisms of infection up to preclinical applications in pneumonia prevention.

In the European Network of Investigators “Triggering Exploratory Research on Myeloid Regulatory Cells – Mye-EUNITER”, which is funded by the EU and coordinated by Prof. Sven Brandau (Immunology, ENO Clinic), 100 scientists from 25 European countries are working on so-called myeloid regulatory cells, a subset of white blood cells. The goal is to achieve systematic and standardised analysis of these cells for characteristic traits and functions of subpopulations in physiology and pathophysiology. The intention is to create a standard for common protocols and harmonising guidelines for analysis and clinical monitoring of MRCs so that the importance of these cells in different pathologies, such as cancer, HIV, hepatitis or psoriasis, can be analysed and compared under uniform conditions. The long-term goal is to create the conditions for regulatory myeloid cells to be used as biomarkers of human disease and to develop novel therapies that work on the principle of targeted functional modulation of these cells.

Molecular and Chemical Cell Biology

Elucidating disease-relevant molecular mechanisms remains the main challenge for biomedical basic research in the 21st century, despite the huge advances that have been made in systemwide data collection and precise manipulation of genetic material. The Molecular and Chemical Cell Biology research programme seeks to elucidate molecular mechanisms of important biological processes using modern cell biology and biochemical methods. Its underlying philosophy is that a deep mechanistic understanding of the fundamental cellular processes is vital in order to understand pathological changes, identify innovative starting points for therapies, and develop new drugs.

It is a research programme that demands a high degree of interdisciplinary collaboration, for which the ZMB offers excellent conditions by bringing together Biology, Chemistry and Medicine in a single centre. A key task of the Molecular and Chemical Cell Biology programme is molecular analysis of cellular signal transduction pathways and molecular switches (protein complexes) that control the direction of subsequent processes at decision points in signal transduction. The focus is particularly on signal transduction pathways that control cell proliferation and molecular regulatory mechanisms of the cell cycle. In Chemistry, for example, new concepts are devised for detailed analysis of molecular mechanisms, signal transduction pathways and the function of molecular switches by providing specific molecules that acutely and selectively intervene in molecular processes and structures.

There has been consistent and targeted development over the years to make the Molecular and Chemical Cell Biology research programme an institutional priority. This has been made possible chiefly through interdisciplinary work on the research programme in Medicine, Biology and Chemistry between the Essen Campus and Essen University Hospital, and through strategic appointments of leading experts. Examples include the inter-faculty appointments of recent years, which have been instrumental in creating a focus on the proposed research programme.

A central research interest of Prof. Elsa Sánchez-García, since 2017 Professor of Computational Biochemistry in the Faculty of Biology, is how molecules control important physiological processes. The theoretical chemist and holder of many awards and distinctions studies molecular interactions in chemical and biological systems, through which she is part of the Molecular and Chemical Cell Biology research programme. In her methodology Professor Sánchez-García works with computer simulations to develop models for the chemical and biochemical processes under examination and from them derive potential approaches for the experimental cooperation partners. When more is known about the interactions between molecules (e.g. proteins or active ingredients), it may be possible to better understand and treat pathological and other processes.

Researchers working with Prof. Perihan Nalbant (Molecular Cell Biology) and PD Dr. Leif Dehmelt (TU Dortmund/Max Planck Institute of Molecular Physiology) identified a molecular mechanism with which human cells can probe the elastic properties of their surroundings. Local contractions are generated with the aid of an intracellular signalling network that produces one-to-two-minute activity pulses in the corresponding positions. The researchers discovered that the measured frequency of the contraction pulses is modulated by the elasticity of the cell’s surroundings.

A very topical and ground-breaking discipline is DNA nanotechnology, which is the focus of the Bionanotechnology group headed by Dr. Barbara Saccà. One of the Saccà group’s current research interests is in development of functional DNA-based nanocontainers for controlled protein loading. As work with their ZMB colleagues Ehrmann, Barcikowski and Sánchez- García has now shown, chemical modification of the inner cavity of such DNA nanocontainers with regio-selective ligands makes it possible to “trap” specific proteins in a DNA container without changing the properties or functions of the protein as a result of containment in the microstructure. This presents future possibilities for specifically isolating in the cell proteins for which there are so far no conventional agents and here influencing signal transduction pathways (including pathological ones).

Despite the biomedical importance of S1 serine proteases, one of the largest and biologically most relevant protease families, only a few generic concepts for producing potent, bioactive, S1 enzyme-family-specific and noncovalent inhibitors exist to date. The research groups of Prof. Markus Kaiser and Prof. Michael Ehrmann have now been able to show that Ahp cyclodepsipeptides are suitable structures for forming tailored serine protease inhibitors, as has been demonstrated in the development of the hitherto most potent inhibitors for human HTRA proteases.

The research groups of Prof. Hemmo Meyer and Prof. Matthias Epple are reporting how nanoparticles can be used as carriers to transport biomolecules like proteins and synthetic molecules through the cell membrane. In their research, the red-fluorescing model protein R-phycoerythrin (R-PE) was taken up by the investigated cell lines where calcium phosphate nanoparticles were used, while no uptake was observed without the carriers. From its red fluorescence the protein could be seen to be intact and functional in all the cell lines. In some cell lines, however, proteolysis could be observed after a few hours from the diminishing intensity of the red fluorescence. In the presence of Bafilomycin A1, an inhibitor of acidification and protein degradation in lysosomes, the fluorescence of R-PE remained intact throughout observation in the investigated cell lines. These results indicate that, despite efficient nanoparticle- mediated uptake of proteins by cells, rapid endolysosomal degradation can prevent the desired (e.g. therapeutic) effect of a protein in a cell.

The research group of UDE honorary professor and ERC award holder Andrea Musacchio at the MPI for Molecular Physiology in Dortmund is investigating the molecular mechanisms of chromosome segregation. The focus is on large macromolecular assemblies called kinetochores, which are composed of more than 30 subunits. Their primary function is to create physical linkages between chromosomes and the mitotic spindle to ensure the correct distribution of chromosomes from a mother cell to its two daughter cells during cell division. Kinetochores also control the cell cycle checkpoint known as the spindle assembly checkpoint (SAC), the primary purpose of which is to halt cell cycle progression if chromosome attachment to the spindle is delayed or derailed by external agents (e.g. small molecules that destroy the mitotic spindle). The primary goal of the Musacchio laboratory is to reconstitute the kinetochore and the SAC function in vitro from the purified components. The group has continued to make major progress towards this goal over the past two years.

The molecular mechanisms that control precise chromosomal segregation and analysis of structure, function and regulation of the kinetochore are also central to the research of Prof. Stefan Westermann. He is interested in how dynamic elements of the cytoskeleton of a cell, the microtubules, can cause controlled movement of the chromosomes. Investigation in this area involves analysis of the molecular structure of the kinetochore and the binding mechanisms to the mitotic spindle, for example by so-called motor proteins. The research recently showed that a force-induced directional switch of a molecular motor enables formation of parallel microtubule bundles – essential for intracellular transport, regulation of cell polarity and growth – after initial isotropic growth.

The Schmuck (Supramolecular Chemistry) and Knauer (Molecular Biology II) research groups have been able to show that functionalisation of tetracationic cyclic peptide (Ka)4 with a weakly basic but highly efficient arginine analogue like guanidiniocarbonyl pyrrole (GCP) completely changes the self-assembly properties of the peptide and thus permits formation of a new class of very efficient synthetic gene transfection vectors. The aggregates formed in this way can be transported into cells thanks to DNA binding to their cationic surface and thus offer potential for development of new gene therapies.

Selected current research projects

Collaborative Research Centre SFB 1093 “Supramolecular Chemistry on Proteins” is entering the next funding phase with Prof. Thomas Schrader (Organic and Supramolecular Chemistry) as its coordinator. The 15 existing groups from Chemistry, Biology and Medicine will be joined by three new research groups, which include the ZMB members Voßkuhl and Westermann. Central to their work is synthesis of large molecules with chemical methods that are designed to act as “molecular tweezers” for protein and are used to analyse biochemical mechanisms.

Research at the UDE Institute for Human Genetics, which is headed by Prof. Bernhard Horsthemke, investigates questions relating to clinical and molecular genetics. The main research interests concern the significance of genetic and epigenetic variations for disease development. Inquiry focuses on differences in gene expression caused by DNA sequence variations or DNA methylation. A particular area of interest is in genomic imprinting. The Institute is currently engaged in nationwide networks to advance two very relevant topics in medicine: Prof. Horsthemke coordinates the BMBF “Network Imprinting Diseases” project, which entered its second funding period in 2015, and the group is also represented in the German Epigenome Programme (DEEP) and “Chromatin-Net – Network on cognitive impairment disorders with defective chromatin dynamics” of the BMBF.

The interdisciplinary nature of the ZMB in representing the UDE’s main research area of Biomedical Sciences is reflected also by the ZMB members Barcikowski, Epple, Knauer, Saccà, Schlücker and Schmuck, who simultaneously belong to the Centre for Nanointegration (CENIDE), where they contribute their expertise to NanoBioMaterials research (see page 19).