Role of pericytes in the immunopathogenesis of pneumococcal meningitis

• Applicants: Professor Dr. Uwe Ködel; Professor Dr. Hans-Walter Pfister
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419675111

• Final Report Year: 2023

Final Report Abstract

Pneumococcal meningitis (PM) is the most common and dangerous form of bacterial meningitis. Every 10th patient dies from this disease, every 2nd survivor suffers from neurological damage. The pathological correlate of these residuals is tissue destruction in various brain regions. The central causal factor for the tissue damage is the massive inflammatory reaction in the central nervous system (CNS) that is regularly observed in this disease. Over the past 20 years, our understanding of the immune pathogenesis of PM has improved significantly. However, there is still uncertainty as to which cell types in the CNS are critical for immune activation. Due to their perivascular localization (vessels are the main entry point for pneumococci) and their numerous pro-inflammatory properties described in cell culture experiments, pericytes could act as “sentinel cells” in pneumococcal infection. In this research project, the importance of CNS pericytes in PM should be examined in more detail. We carried out investigations in mono- and co-culture systems (with macrophages) of primary CNS pericytes and in two established animal models of PM. The key findings of our studies were as follows: [i] both murine and human pericytes responded to pneumococcal challenge by releasing selected cytokines. [ii] This cytokine release was independent of the pneumococcal serotype, but dependent on the bacterial toxin pneumolysin. [iii] The cytokine release could be dramatically increased by the macrophage-derived cytokine interleukin-1β. [iv] In the course of experimental PM, a loss of the pericyte population could be observed regionally. [v] Pharmacological depletion of pericytes in the zebrafish embryo model of PM resulted in increased cerebral edema and mortality. Accordingly, in a meningitis model in adult mice, a more pronounced blood-brain barrier disruption and leukocyte infiltration was observed after genetic pericyte ablation, which was paralleled by an unfavorable course of the disease. The stronger leukocyte infiltration was accompanied by a higher expression of chemotactic factors in the brain of mice with a pericyte deficiency. Our investigations thus showed that CNS pericytes play a protective role in PM by impeding leukocyte migration and preventing damage to the blood-brain barrier. Maintaining the integrity of the pericyte population could therefore be a potential goal for a new therapeutic strategy in PM.

Publications

• Neurological infections in 2019: challenges, solutions, and open questions. The Lancet Neurology, 19(1), 19-20.
  Koedel, Uwe; Klein, Matthias & Pfister, Hans Walter
  
• Community-acquired bacterial meningitis. The Lancet, 398(10306), 1171-1183.
  van de Beek, Diederik; Brouwer, Matthijs C.; Koedel, Uwe & Wall, Emma C.
  
• The Glymphatic System: a Potential Key Player in Bacterial Meningitis. mBio, 13(6).
  Oggioni, Marco Rinaldo & Koedel, Uwe
  
• The role of plasminogen activator inhibitor-2 in pneumococcal meningitis. Acta Neuropathologica Communications, 10(1).
  Teske, Nina C.; Engelen-Lee, Joo-Yeon; Dyckhoff-Shen, Susanne; Pfister, Hans-Walter; Klein, Matthias; van de Beek, Diederik; Kirschning, Carsten K.; Koedel, Uwe & Brouwer, Matthijs C.