Dr. Jekyll and Mr. Hyde
A systems biology approach for the treatment of nosocomial infections with Candida albicans: From an commensal organism to a life-threatening pathogen
Candida albicans is the single most important human fungal pathogen, causing up to 70% of all fungal nosocomial infections. Although this fungus usually is a commensal and frequently found on the skin and mucosa of healthy humans, it can become an even life - threatening pathogen in patients with a compromised immune system. As most C. albicans infections are caused by strains that already colonized the patient and not by those acquired in the hospital, in critical care units antimycotics are prophylactically given to prevent the outbreak of the infection. However, this regime leads to selection of resistant strains and does not take into account the individual predisposition of the patient.
In this project we aim at an improved, detailed understanding of the interaction between the opportunistic pathogen Candida albicans and host cells. We established an infection model comprising epithelial cells, which were colonized by the yeast C. albicans, and added neutrophils as representatives of the immune system. Thus, we can mimic both the commensal and the infectious state of C. albicans and can follow the development of the infection. From gene expression and protein analysis of host cells and pathogens, analysis of cell culture supernatants with respect to metabolites and signaling compounds and perturbations by chemical inhibitors and single gene deletion mutants we obtain comprehensive information on the mutual interactions on the molecular scale.
This information is to be used to establish and validate a multi-scale mathematical model. In each organism metabolic and signal transduction reactions are highly connected and interwoven and form robust networks, which allow the organisms the survival under different conditions and defence against stress and harmful situations. Signal and mass flow through these networks is adjusted and is dependent on critical, central nodes, which may be variable according to the needs of the organism in the respective environmental condition. The mathematical model should allow predictions of those central nodes, because they could be addressed by therapeutic strategies.
Thus, in this project experimental and theoretical approaches are connected with the aim of in-depth understanding of the processes governing the interactions between human hosts and opportunistic pathogens. The project is funded by the BMBF.