Fate and function of border-associated macrophages in pneumococcal meningitis

• Applicant: Professor Dr. Uwe Ködel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432002731

• Final Report Year: 2024

Final Report Abstract

Pneumococcal meningitis (PM) is the most common and dangerous form of bacterial meningitis in Europe. One in 10 patients dies from this disease, and half of the survivors suffer from neurological sequelae. The main cause of this is the massive inflammatory response triggered by pneumococcal infection, which leads to cerebral tissue damage. To date, it remains unclear which cell types are crucial for the induction and regulation of the immune response in PM. It was previously assumed that meningeal macrophages, the classical tissueresident sentinel cells of the immune system in the leptomeningeal space, control the immune defense against the pathogen. However, the relevance of this concept has been called into question by two studies reporting only minor (and partly contradictory) effects of macrophage depletion on the inflammatory response in PM. In this research project, we aimed to investigate the function and behavior of meningeal macrophages in PM in more detail. To do this, we primarily conducted studies using an established animal model of PM, which closely mimics the neuropathological changes observed in humans. The key results of our studies were as follows: [i] Pneumococcal infection led to a significant reduction in the meningeal macrophage population. [ii] In contrast to our observations in murine and human cell culture systems, macrophage loss was not due to pyroptotic cell death, but was similarly dependent on the presence of the bacterial toxin pneumolysin. [iii] Independently, pharmacological inhibitors of pyroptosis exerted protective effects in a clinically relevant mouse model, likely due to their anti-inflammatory effects through inhibition of interleukin (IL)-1beta production. [iv] Depletion of meningeal macrophages had little impact on the early course of the disease but was associated with pronounced neuropathological changes and increased mortality later in the disease course. This seems to be due to a persistently strong immune response after the initiation of antibiotic treatment. [v] One possible explanation for the limited effects of macrophage depletion on immune activation (the early course of the disease) could be, as cell culture studies showed, that even a few macrophages and the IL-1beta they release are sufficient to instruct fibroblasts to produce large amounts of pro-inflammatory factors. Thus, our investigations demonstrated that meningeal macrophages play a protective role in PM: they regulate the resolution of the inflammatory response, thereby counteracting inflammationinduced tissue damage. Preserving the integrity of the macrophage population could therefore be a potential target 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.
  
• Macrophage pyroptosis aggravates inflammation and pathology in murine pneumococcal meningitis. Oral 941, ECCMID 2021, Online
  P. Händle, S. Dyckhoff-Shen, O. Gorka, B. Angele, H.-W. Pfister, M. Klein, O. Groß, C. Kirschning & U. Koedel
  
• Meningeal cells participate in regulating the immune response to pneumococcal infection. P1696 ECCMID 2022, Lissabon
  L. Ercegovac, S. Dyckhoff-Shen, B. Angele, S. Hammerschmidt, T. Kohler, M. Klein, H.W. Pfister & U. Koedel
  
• 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.
  
• Macrophages guide the immune response of meningeal cells to Streptococcus pneumoniae exposure through IL-1β secretion. P1293, ECCMID 2023, Copenhagen
  P. Beckenbauer, S. Dyckhoff-Shen Shen, B. Angele, M. Klein, S. Hammerschmidt, H.-W. Pfister & U. Koedel
  
• Intravenous Immunoglobulins (IVIG) inhibit Streptococcus pneumoniae-induced macrophage activation and death in vitro, but lack beneficial effects in a mouse meningitis model in vivo. O2527. ECCMID P3857, Barcelona
  S. Dyckhoff-Shen, P. Lagler, G. Christensen, B. Angele, H.-W. Pfister, S. Hammerschmidt , M. Klein & U. Koedel