Project Details
Projekt
Role of pericytes in the immunopathogenesis of pneumococcal meningitis
Subject Area
Molecular and Cellular Neurology and Neuropathology
Clinical Neurology; Neurosurgery and Neuroradiology
Clinical Neurology; Neurosurgery and Neuroradiology
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 419675111
Pneumococcal meningitis (PM) is one of the most serious infectious diseases of the central nervous system (CNS). Pneumococcal CNS infection generates a massive inflammatory reaction which can cause brain damage and thus contributes to unfavorable disease outcome. Experimental work has provided evidence that postcapillary venules are the primary site of entry into the cerebrospinal fluid (CSF) for both, S. pneumoniae and blood-borne leukocytes. Postcapillary venules consist of a layer of specialized endothelial cells, a basement membrane, and pericytes. The vessels are surrounded by a fluid-filled space populated by immunocompetent cells, such as macrophages or mast cells. Recent studies showed no or only partial effects of mast cell deficiency or macrophage depletion in PM models, suggesting contribution of additional cells residing in the perivascular niche to immune activation upon pneumococcal CSF infection. In pilot experiments, we observed that brain pericytes responded to S. pneumoniae challenge by altered cytokine release. By using an inhibition strategy, we found evidence that pericytes recognize the presence of S. pneumoniae by means of Toll-like receptors. Moreover, immunohistochemical investigations on murine brain sections suggested substantial changes in the staining pattern for established pericyte markers during the course of PM. Based on these data, we hypothesize that pericytes could be regulators of the hyper-inflammatory reaction and related tissue damage in PM. In the first place, we plan to characterize the functional role of pericytes in pneumococcal infection in vitro. We will compare the responsiveness of primary murine brain pericytes upon exposure to different serotypes of S. pneumoniae with that of human brain pericytes in more detail. Since pericytes have been suggested to be multipotent, we will also evaluate whether pericytes adopt a macrophage-like phenotype upon pneumococcal challenge. We will further investigate whether pericytes are capable of modulating the response of macrophages to pneumococcal stimulation using contact and non-contact co-culture systems. As a next step, we plan to determine the functional importance of pericytes for the clinical course of PM in a mouse model. First, we will assess pericyte coverage of brain vessels using PDGFRbeta-eGFP transgenic reporter mice, double immunostaining with pericyte and endothelial markers, as well as a combination of both techniques. To get more insight into their functional role in PM, we will then evaluate the impact of pericyte depletion on the disease phenotype by using a triple strategy: by intrathecal administration of the PDGFR inhibitor imatinib, by using transgenic PDGFRbeta-tk mice (treated intracisternally with ganciclovir), and by using PDGF-B retention motif knockouts (Pdgfbetaret/ret). In our opinion, this research project will markedly improve our knowledge about mechanisms of immunoregulation within the CNS.
DFG Programme
Research Grants
