Research association coordinated by FAU investigates epigenetic regulation of the immune system
To differentiate friend from foe and to combat attacks by pathogens the immune system needs numerous messenger substances. They pass on information and in doing so control the body’s defence system against infection. An international research association is currently investigating these messenger substances and the interactions between them at a molecular level. The association is one of nine selected research projects to receive funding amounting to 770,000 euro over the next three years as part of the European Commission’s Infect-ERA Programme. The project is coordinated by Prof. Dr. Christian Bogdan from the Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene at FAU.
The association’s researchers are investigating a recently discovered immune system regulatory mechanism they had observed during joint preliminary work. Their work focuses on three messenger substances: Interleukin-4 (IL-4), interferon-γ (IFN-γ) and tumour necrosis factor (TNF). All three messenger substances are of significant importance to infection defence, although they control it in different ways. TNF and IFN-γ stimulate scavenger cells (macrophages), which are essential elements of defence against so-called intracellular pathogens. These types of pathogen are bacteria or single-celled organisms such as Salmonella and Leishmania that attack body cells. IL-4, on the other hand, stimulates tissue repair and is required to control worm infections. It usually inhibits the defence system against pathogens that penetrate cells. “We observed that TNF and IFN-γ block the effect of IL-4”, explains Prof. Dr. Christian Bogdan. “That is an important component of their protective effect, for instance when killing Leishmania”, says the FAU researcher and association coordinator.
The project’s objective now is to decrypt the mechanism behind the recently discovered effect of TNF and IFN-γ, which so far is understood only to a certain extent. Research initially assumed that the two messenger substances blocked the effect of IL-4 at the level of transcription factors, which are responsible for relaying signals. Preliminary work, however, has revealed that the central location of attack lies a regulatory level lower, namely the exposure of the respective gene regions to transcription factors. In order to read genes, the proteins that package DNA called histones need to be chemically modified, which allows the chromatin to open and exposes the binding sites for transcription factors. TNF or IFN-γ can inhibit precisely these epigenetic processes for specific macrophage genes that are activated by IL-4.
The association’s researchers are aiming to define the regulators, signals and metabolic processes that lead to chemical modification of histones. In combination with DNA, these important proteins form chromatin, the material chromosomes and the associated genetic information are composed of. The researchers are also hoping to investigate the effects of these processes on infections caused by Salmonella or Leishmania and whether the pathogens also influence the epigenetic regulation of gene expression in macrophages in order to avoid being killed by scavenger cells. Furthermore, they hope to clarify whether infection control can be improved by intentionally deactivating specific chromatin regulators.
Funding in Europe
This German-Austrian-Italian research association project is one of 124 suggested projects that successfully completed a two-stage application procedure in the fourth call of the Infect-ERA initiative. Infect-ERA is a programme for promoting research on infectious diseases in the European Research Area (ERA). It is funded by the European Commission and national partner organisations in Austria, Belgium, Denmark, France, Germany, Hungary, Israel, Poland, Portugal, Romania and Spain.
Prof. Dr. Christian Bogdan
Phone: +49 9131 8522551