SP9 Disease tolerance: Preventing progression of infection to sepsis with organ failure

Project Leader: Michael Bauer

Background and previous work
Strategies to deal with pathogens that act to prevent or resolve tissue and organ damage carry great potential to revolutionise treatment of infectious diseases in the light of antibiotic resistance. The recently proposed concept of "disease tolerance" reflects a defence strategy depending on metabolic adaptation that limits fitness costs of infection irrespective of the pathogen burden [135]. Moreover, there is increasing evidence for distinct and opposite response mechanisms induced by specific PAMPs representing constituents either from fungal wall or bacterial membrane resulting in training (β-glucan) or tolerance (endotoxin). Examples for metabolic adaptation encompass diverse pathways that are largely unexplored and require cell-type specific strategies to interfere with critical signalling events.

Specific aims and working programme
Using methods of systems biology (epigenetic reprogramming, transcriptional and metabolomic profiling, applied to human liver organoid cultures we aim to address whether there is a) a specific transcriptomic pattern in monocytic cells following adherence and transmigration to (activated) endothelium and whether b) the proposed monocytic stress response is specifically altered by previous exposure to different PAMPs or DAMPs (i.e. training or tolerance) in a dose-dependent manner. From these results stimuli and dependent signalling pathways become apparent that can be used to attain a more favourable monocytic phenotype. Our second generation PhD candidate will test in a cell-specific manner, regulation of cellular stress responses and signalling events of monocytes adherent in the liver and how their phenotype can be manipulated to improve or prevent paracrine tissue damage in liver parenchyma.