Immunoregulatory role of mast cells in infections of the cerebrospinal fluid compartment: Investigations on a mouse model of pneumococcal meningitis

• Applicant: Professor Dr. Uwe Ködel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 243354071

Bacterial meningitis is among the top 10 causes of infection-related deaths worldwide. The most frequent etiologic agent in Europe is Streptococcus pneumoniae. Pneumococcal infection of the cerebrospinal fluid (CSF)-filled subarachnoid space generates one of the most powerful inflammatory responses known in medicine. Although the molecular mechanisms underlying this response have been largely characterized, there is still uncertainty about the cellular initiators of meningeal inflammation. In pilot experiments aimed at getting first insight into the role of mast cells in pneumococcal meningitis, we observed an unexpected, marked increase in CSF pleocytosis in mast cell deficient W/W-v mice which was reversible by mast cell reconstitution. Analyses of brain cytokine expression revealed a parallel increase in interleukin (IL)-1ß levels. Treatment of W/W-v mice with an IL-1 receptor antagonist restored CSF leukocyte counts to levels seen in wild type mice. These data suggest that, in pneumococcal meningitis, mast cells may limit neutrophilic inflammation through control of IL-1ß bioactivity. The mechanism(s) underlying the restriction of IL-1ß levels by meningeal mast cells, however, need(s) to be clarified. The aim of this research project is to definitively characterize the function of mast cells in pneumococcal meningitis. In the first place, we plan to evaluate the phenotype of an additional mast cell-deficient mouse strain, the W-sh mice, with pneumococcal meningitis. We expect that W-sh mice will display the disease phenotype of W/W-v mice, providing further evidence that the phenotype is due to mast cell deficiency rather than other mouse strain-related factors. Moreover, it would enable us to use W-sh mice in further experiments. W-sh mice are fertile and on the well-studied C57BL/6 genetic background, facilitating the use of transgenic mouse lines for the planned mast cell reconstitution experiments. In the next step, we plan to identify the mechanisms responsible for the anti-inflammatory activity of mast cells in pneumococcal meningitis, thereby focussing on the role of mast cell-derived anti-inflammatory cytokines (e.g., IL-10) and serine peptidases (like tryptase or chymase), the latter of which have recently been shown to be able to degrade several cytokines into inactive molecules. Finally, we plan to investigate the response of cultured mast cells upon pneumococcal challenge. In doing so, bone marrow-derived mast cells shall be cultured under conditions mimicking features of the CSF-filled subarachnoid space. These cells are planned to be used for investigations of [i] their impact on the pneumococci-induced IL-1ß release by murine macrophages, as well as [ii] their potential to degrade mature IL-1ß. In our opinion, this research project will markedly improve our knowledge about mechanisms of immunoregulation within the central nervous system.

• DFG Programme: Research Grants