Anmerkungen:
Tag der Verteidigung: 05.12.2023
Zusammenfassungen in deutscher und englischer Sprache
Beschreibung:
The complex systemic inflammatory response to invading pathogens usually consists of a sequence of pro-inflammatory reactions, followed by a phase of diminished inflammatory responses, in which monocytes enter a cellular state called monocyte tolerance. To improve therapeutic opportunities, it would be important to differentiate monocytes according to a tolerant or non-tolerant cell state for targeted therapy. Additionally, medium chain fatty acids (MCFAs) like decanoic acid possess pro-inflammatory immune modulating capacity and could thereby provide a potential treatment option for the rescue of monocytes from the tolerant cell state. This doctoral thesis investigated the capability of live Staphylococcus aureus bacteria to induce the tolerant cell state in human monocytes isolated from blood in pre- and restimulation infection experiments along with a modulation by decanoic acid by analysis of gene expression changes via RNA-AmpliSeq. Additionally, transcriptional responses of monocytes derived from 10 patients with S. aureus bacteremia after ex vivo stimulation with S. aureus were analysed for signs of tolerance development. It was found that S. aureus stimulation in vitro induced the tolerant cell state in human monocytes, accompanied by broad changes in gene expression, shifting from an early pro-inflammatory to a late anti-inflammatory response, accompanied by unresponsiveness towards secondary stimuli. However, in monocytes isolated from patients with blood-culture confirmed S. aureus bacteremia, no signs of the tolerant cell state were found. Induction of the tolerant cell state was also shown in THP-1 cells by stimulation with Pam3CysK and S. aureus and proteomic and glycoproteomic analysis identified potentially interesting protein expression changes associated with this cell state. The transcriptional signature of the tolerant cell state was to some extent modified by addition of decanoic acid, resulting in the re-expression of some tolerizable genes.