Molecular identification and characterization of novel immune defense mechanisms for sensing bacterial signal peptides

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Because of the steady increase in multidrug-resistant bacteria accurate characterization of the immune response to bacterial infection is becoming increasingly important, as a better understanding of the underlying molecular processes can contribute to the development of new therapeutic treatment strategies for humans and animals. In the project proposal, we aim to investigate the contribution of a new large group of bacterial peptides to immune defense. N-terminally formylated peptide fragments are important triggers of immune responses in bacterial infections. Until now, it has been generally assumed that their recognition is mediated exclusively by formyl peptide receptors (FPRs). New results Bufe lab show that there must be additional, previously unknown receptors that contribute to their perception. In a joint effort, the Bufe and Bischoff labs already succeeded in identifying some possible candidates. To this end, various FPR-related receptors were tested with a selection of peptides and bacterial supernatants. Some of these receptors could indeed be activated by formyl peptides. In the proposal, the team intends to use the high-throughput microscope to understand the pharmacological and physiological immune responses that bacterial signaling peptides elicit through these additional receptors. To identify the best activators for the different receptors the receptors will be challenged with peptides from a peptide library in the Bufe lab and different bacterial supernatants from a strain collection in the Bischoff lab. Prototypic stimuli will then be used to investigate the physiological significance of these alternative detection pathways for the immune defense of neutrophil granulocytes against bacteria. To distinguish between FPR-dependent and FPR-independent signal transduction pathways, data from CRISPR/Cas9 modified mouse and human cell lines be compared to the responses of corresponding primary isolated cells.