Hupp, Sabrina; Förtsch, Christina; Graber, Franziska; Mitchell, Timothy J; Iliev, Asparouh I (2022). Pneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis. Nature communications, 13(1), p. 5032. Nature Publishing Group 10.1038/s41467-022-32624-2
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy 04 Faculty of Medicine > Service Sector > Institute of Pathology 09 Interdisciplinary Units > Microscopy Imaging Center (MIC) |
UniBE Contributor: |
Hupp, Sabrina, Graber, Franziska, Iliev, Asparouh Iliev |
Subjects: |
600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology |
ISSN: |
2041-1723 |
Publisher: |
Nature Publishing Group |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
29 Aug 2022 13:14 |
Last Modified: |
05 Dec 2022 16:23 |
Publisher DOI: |
10.1038/s41467-022-32624-2 |
PubMed ID: |
36028511 |
BORIS DOI: |
10.48350/172446 |
URI: |
https://boris.unibe.ch/id/eprint/172446 |
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