Systematic causal research at Charité and Tel Aviv University
Berlin, 05.11.2020 – Over the next six years, working groups at Charité – Universitätsmedizin Berlin and Tel Aviv University will investigate how invasive fungal pathogens can escape treatment and develop tolerance to antimycotic substances. Fundamental knowledge about pathogenic fungi on the one hand and discoveries at the level of cell metabolism on the other hand come together in this jointly managed project. A Synergy Grant from the European Research Council (ERC) supports the extensive project with a total of 9.7 million euros.
Fungal infections are widespread and, in many cases, not life-threatening. However, invasive fungal infections, which can contribute to sepsis – a severe, systematic reaction of the organism to an uncontrolled infection – are an exception. Fungal diseases of this kind have a mortality rate of up to 50 percent, are usually difficult to treat and are associated with at least 1.6 million deaths annually. In contrast to bacterial infections, for which several antimicrobial drugs are available, only three specific classes of agents have been shown to be clinically effective against invasive fungal infections. One of the reasons why so few effective drugs are available is the similarity between human and mammalian cells and fungal cells. Accordingly, there are only a few fungus-specific targets for drugs.
What is more, not only are very few anti-fungal drugs available, but the effectiveness of these drugs is also decreasing. For example, about half of the invasive infections caused by Candida albicans, the so-called thrush fungus and most common human pathogens, cannot be effectively controlled by fluconazole, the most used antimycotic in this situation. Therapy failures like this can be partly explained by tolerance or even resistance of the fungal pathogens to anti-fungal drugs. This allows fungal cells to continue growing despite treatment.
The teams led by Prof. Dr. Markus Ralser, Director of the Institute of Biochemistry and head of the Biochemistry and Systems Biology of Metabolism research group at the Charité, and Prof. Dr. Judith Berman, head of the research group at the Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences at the University of Tel Aviv, now want to find out exactly what causes the failure of fungal treatment. One of the central hypotheses here is that the cause may be found in the metabolic process. “We have already observed in studies that different cell types work together by exchanging metabolites, such as nutrients, and thus jointly develop tolerance,” explains Prof. Ralser. “This metabolic cooperation leads to an alignment of the cells. We have indications that this metabolic heterogeneity could be a key to processes such as drug resistance or tolerance. Inhibitors of metabolic pathways also appear to influence the stress survival of some cells”.
The research teams in Berlin and Tel Aviv will now investigate the underlying biological mechanisms in detail. “The situation with invasive fungal pathogens is fundamentally different from the situation with antibiotic-resistant bacteria,” as Prof. Berman describes. “In problematic bacterial infections, pathogens often acquire mutations that make them resistant to antibiotics. However, resistance in pathogenic fungi is not so frequent and does not spread as quickly. Here we find that fungal cells become heterogeneous and adapt to their environment, although some of the cells continue to grow slowly even under the influence of an anti-fungal drug. If we examine these growing cells, we see that drug-resistant and non-resistant cells grow in a similar way to the original fungal strains. Resilience, or resistance, is thus created in the cells themselves and is not caused by similar types of mutations as is the case with bacterial infections”.
In a highly interactive work programme, Prof. Berman and Prof. Ralser will now test thousands of fungal strains for drug resistance and compare their properties at the metabolic level. To this end, they will work with clinicians and biologists across Europe, Canada and the United States. Their common goal is to decipher the molecular pathways that explain drug resistance in fungal diseases. They also want to develop new concepts and lead compounds that prevent disease-causing fungal cells from increasing tolerance or resilience to drugs. The scientists want to contribute to the development of new antifungal agents and combination therapies that are effective against deadly invasive fungal infections.
Prof. Dr. Markus Ralser studied genetics and molecular biology in Salzburg, Austria and completed his PhD in the field of neurodegenerative diseases at the Max Planck Institute (MPI) for Molecular Genetics in Berlin. After training in mass spectrometry at the VU Amsterdam, Netherlands, he founded a junior group at the MPI for Molecular Genetics in Berlin. In 2011 he moved to the University of Cambridge in Great Britain. Since 2013 he has been group leader at the Francis Crick Institute in London. In 2018 he was appointed Einstein Professor of Biochemistry and since then he has been one of two heads of the Department of Biochemistry at the Charité. His work focuses on central carbohydrate and amino acid metabolism, for example the evolutionary origin of carbohydrate metabolism, the metabolic response to oxidative stress, or the use of self-establishing yeast communities to study nutrient exchange. His work has received several awards, including the EMBO Gold Medal, the BioMed Central Resarch Award, the Starling Medal and the Colworth Medal.
Prof. Dr. Judith Berman received her PhD from the Faculty of Biology at the Weizmann Institute of Science in Israel and began her work as Associate Professor at the University of Minnesota. A short time later she was able to accept a professorship at McKnight University, Department of Genetics & Cellular Biology. In 2012 she accepted a professorship in the Department of Molecular Cell Biology at the University of Tel Aviv, Israel. Prof. Berman is a world leading expert in the field of fungal tolerance research and has received numerous awards and honours. She is a member of the European Organisation for Molecular Biology and the Genetics Society of America, a Fellow of the American Academy for the Advancement of Science and a Fellow of the American Academy of Microbiology (ASM).
ERC Synergy Grant: The European Research Council supports teams of two to four excellent scientists in Synergy Grants. The projects should lead to discoveries at the interfaces between disciplines and to substantial progress at the frontiers of knowledge. It is a prerequisite that the project is only possible through the cooperation of the researchers. The maximum funding amount per project is ten million euros for a period of up to six years.