Role of purinergic signalling in the immunopathogenesis of pneumococcal meningitis

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Pneumococcal meningitis is the most common and most serious form of bacterial meningitis in adults. Even under best medical care, 15 - 20 per cent of patients die of the disease and up to one third of survivors retain neurologic deficits. These neurologic sequelae reflect structural injury to diverse brain structures. This brain injury is thought to be largely caused by the massive neutrophilic inflammatory reaction which is only little modified by antibiotic therapy over days even though complete CSF sterilization occurs within hours. We hypothesized that the delay in resolution of inflammation is - at least partly - the consequence of a vicious cycle in which inflammation-induced cell injury leads to the release of endogenous alarmins that drive the inflammatory response, causing further damage. While there is now a rapidly growing list of alarmins in the literature, extracellular ATP (eATP) belongs to the best characterized members of this molecule family. In recent pilot experiments, our group has obtained evidence that [i] diverse cell types release ATP into the extracellular space upon exposure to pneumococci, and [ii] eATP contributes to the production of interleukin-1beta, an important immune regulator in pneumococcal meningitis, by pneumococci-stimulated macrophages. Moreover, a pilot gene expression analysis of mouse brains has suggested that profound alterations in purinoceptor expression occur during the course of pneumococcal meningitis. The focus of this research proposal is to characterize the function of eATP and purinergic signalling in the pathogenesis of pneumococcal meningitis. Most experiments will be done using our well-established mouse model which closely mimics the clinical, immunological, and neuropathological features of human pneumococcal meningitis. More in detail, we plan to identify the cellular sources and release mechanisms of ATP in the mouse model as well as in cell culture systems. Next, the protein expression pattern of purinoceptors shall be investigated in the mouse model. Finally, we plan to assess the functional significance and the modes of action of eATP and ATP-related signalling in the host defense, immune regulation, and the development of intracranial complications (brain injury) by using selective antagonists as well as mice lacking specific purinoceptors. In our opinion, this research project will markedly improve our knowledge about the mechanisms of the immunoregulation within the central nervous system, thereby revealing new targets for adjuvant therapy of pneumococcal meningitis.