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Updated: Aug 30, 2025
Characterization of Inflammatory Responses During Intranasal Colonization with Streptococcus pneumoniae
Published on: January 17, 2014
Pneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis
Sabrina Hupp1, Christina Förtsch2, Franziska Graber3
1Institute of Anatomy, University of Bern, Bern, Switzerland. sabrina.hupp@ana.unibe.ch.
Abstract:
In pneumococcal meningitis, bacterial growth in the cerebrospinal fluid results in lysis, the release of toxic factors, and subsequent neuroinflammation. Exposure of primary murine glia to Streptococcus pneumoniae lysates leads to strong proinflammatory cytokine and chemokine production, blocked by inhibition of the intracellular innate receptor Nod1. Lysates enhance dynamin-dependent endocytosis, and dynamin inhibition reduces neuroinflammation, blocking ligand internalization. Here we identify the cholesterol-dependent cytolysin pneumolysin as a pro-endocytotic factor in lysates, its elimination reduces their proinflammatory effect. Only pore-competent pneumolysin enhances endocytosis in a dynamin-, phosphatidylinositol-3-kinase- and potassium-dependent manner. Endocytic enhancement is limited to toxin-exposed parts of the membrane, the effect is rapid and pneumolysin permanently alters membrane dynamics. In a murine model of pneumococcal meningitis, mice treated with chlorpromazine, a neuroleptic with a complementary endocytosis inhibitory effect show reduced neuroinflammation. Thus, the dynamin-dependent endocytosis emerges as a factor in pneumococcal neuroinflammation, and its enhancement by a cytolysin represents a proinflammatory control mechanism.
Insights
Pneumolysin, a toxin from Streptococcus pneumoniae, enhances bacterial entry into brain cells, worsening meningitis. Inhibiting this toxin or cell entry reduces neuroinflammation, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Pneumococcal meningitis causes neuroinflammation due to bacterial factors released in cerebrospinal fluid.
- Proinflammatory responses in glia are triggered by Streptococcus pneumoniae lysates, mediated by the innate receptor Nod1.
- Dynamin-dependent endocytosis is implicated in this neuroinflammation by facilitating ligand internalization.
Purpose of the Study:
- To identify the specific bacterial factors responsible for enhancing endocytosis in pneumococcal meningitis.
- To elucidate the mechanism by which these factors promote endocytosis and neuroinflammation.
- To evaluate the therapeutic potential of targeting endocytosis in a murine model of pneumococcal meningitis.
Main Methods:
- Exposure of primary murine glia to Streptococcus pneumoniae lysates.
- Assessment of cytokine and chemokine production.
- Inhibition of Nod1 and dynamin.
- Identification of pneumolysin's role using pore-incompetent mutants.
- Analysis of membrane dynamics and endocytosis.
- Treatment of mice with chlorpromazine in a meningitis model.
Main Results:
- Streptococcus pneumoniae lysates induce proinflammatory cytokine and chemokine production in glia, blocked by Nod1 inhibition.
- Lysates enhance dynamin-dependent endocytosis, and its inhibition reduces neuroinflammation.
- Pore-competent pneumolysin was identified as a key factor enhancing endocytosis, dependent on dynamin, PI3K, and potassium.
- Pneumolysin rapidly and permanently alters membrane dynamics at toxin-exposed sites.
- Chlorpromazine treatment reduced neuroinflammation in a murine model of pneumococcal meningitis.
Conclusions:
- Dynamin-dependent endocytosis is a significant factor in pneumococcal meningitis-associated neuroinflammation.
- Pneumolysin's ability to enhance endocytosis represents a novel proinflammatory mechanism.
- Targeting pneumolysin-mediated endocytosis offers a potential therapeutic strategy for pneumococcal meningitis.
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