Investigations for the immunomodulatory and neuroregenerative role of formyl peptide receptors after bacterial meningitis

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The central nervous system (CNS) is protected by the blood-brain barrier and the innate immune system against invading pathogens. An infection of the CNS in the form of bacterial meningitis is despite antibiotic therapy still associated with a high mortality rate and long-term sequelae. For the detection of the pathogens by the innate immune cells pattern recognition receptors are responsible. An important representative of the PRR is the family of formyl peptide receptors (FPR). The chemotactic G-protein-coupled receptors are activated by n-formyl peptides of prokaryotic bacterial cell wall or by mitochondrial components released in the context of tissue injury. Furthermore, the FPR are activated by a broad spectrum of pro- or anti-inflammatory ligands. Interestingly, it was shown that the FPRs are mediated the anti-inflammatory activity of the endogenous protein annexin A1. For annexin A1 and its bioactive fragment Ac2-26, a positive influence of the inflammatory processes in the course of multiple sclerosis was detected. Our previous work shown for the FPR-deficient mice an increase of mortality and inflammatory response after bacterial meningitis compared to wildtype mice. With the present application, the immunomodulatory potential of the FPR should be investigated in a mouse model of Streptococcus pneumoniae meningitis, because the inflammatory response an essential role in the development of both acute and long-term damage is attributed. For this purpose, wildtype and receptor-deficient mice are intraperitoneally injected with Ac2-26 after the induction of pneumococcal meningitis. Subsequently, the modulation of the inflammatory response and regeneration of the neuronal damage should be characterized in the form of hippocampal neurogenesis. Possible functional consequences of histological changes should be checked by means of neuropsychological test (Morris Water Maze). The in vivo studies are complemented by in vitro studies in order to better understand the differences between the different ligands with respect to their signal transduction pathways and the associated effect on the inflammatory response. In addition, we plan to perform a broad study of the Ac2-26 effect on the whole organism. The received findings of the application could provide new approaches for novel adjuvant treatment strategies for bacterial meningitis.