ArticlePLoS pathogens2021
Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin.
Article in PLoS pathogens, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 37 citations in OpenAlex.
- Bioengineered Extracellular Vesicles Mitigate Neuroinflammation by Neutralizing Pneumolysin and Delaying Disease Onset in Experimental Pneumococcal Meningitis.Journal of extracellular vesicles · 2026Article
- Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization.PLoS pathogens · 2026Article
- Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion.Nature communications · 2026Article
- The meninges as a neuroimmune interface: structure, barriers and roles in CNS disease.Fluids and barriers of the CNS · 2026Review
- Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization.bioRxiv : the preprint server for biology · 2026Article
- Recent advancements in pediatric purulent meningitis: diagnosis and treatment.Italian journal of pediatrics · 2026Review
- Neuraminidase A controls pneumococcal recognition and fate: deficiency enhances immune sensing and intracellular survival, while treatment promotes phagocytic clearance.Immunotherapy advances · 2026Article
- Fulminant Multidrug-ResistantMicroorganisms · 2025Article
- Bacteriophage-derived endolysins restore antibiotic susceptibility in β-lactam- and macrolide-resistant Streptococcus pneumoniae infections.Molecular medicine (Cambridge, Mass.) · 2025Article
- Streptococcus pneumoniae epidemiology, pathogenesis and control.Nature reviews. Microbiology · 2025Review
- Astrocyte-derived complement C3 facilitated microglial phagocytosis of synapses in Staphylococcus aureus-associated neurocognitive deficits.PLoS pathogens · 2025Article
- Understanding the mechanisms ofTissue barriers · 2025Review
- Review
- Article
- Post-Meningitic Syndrome: Pathophysiology and Consequences of Streptococcal Infections on the Central Nervous System.International journal of molecular sciences · 2024Review
- The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells.iScience · 2024Article
- Klebsiella pneumoniae peptide hijacks a Streptococcus pneumoniae permease to subvert pneumococcal growth and colonization.Communications biology · 2024Article
- Pushing the Resolution Limit of Stimulated Emission Depletion Optical Nanoscopy.International journal of molecular sciences · 2023Review
- Pore-forming activity ofInfection and immunity · 2023Article
- Addition of daptomycin for the treatment of pneumococcal meningitis: protocol for the AddaMAP study.BMJ open · 2023Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neuronal damage is a major consequence of bacterial meningitis, but little is known about mechanisms of bacterial interaction with neurons leading to neuronal cell death. Streptococcus pneumoniae (pneumococcus) is a leading cause of bacterial meningitis and many survivors develop neurological sequelae after the acute infection has resolved, possibly due to neuronal damage. Here, we studied mechanisms for pneumococcal interactions with neurons. Using human primary neurons, pull-down experiments and mass spectrometry, we show that pneumococci interact with the cytoskeleton protein β-actin through the pilus-1 adhesin RrgA and the cytotoxin pneumolysin (Ply), thereby promoting adhesion and invasion of neurons, and neuronal death. Using our bacteremia-derived meningitis mouse model, we observe that RrgA- and Ply-expressing pneumococci co-localize with neuronal β-actin. Using purified proteins, we show that Ply, through its cholesterol-binding domain 4, interacts with the neuronal plasma membrane, thereby increasing the exposure on the outer surface of β-actin filaments, leading to more β-actin binding sites available for RrgA binding, and thus enhanced pneumococcal interactions with neurons. Pneumococcal infection promotes neuronal death possibly due to increased intracellular Ca2+ levels depending on presence of Ply, as well as on actin cytoskeleton disassembly. STED super-resolution microscopy showed disruption of β-actin filaments in neurons infected with pneumococci expressing RrgA and Ply. Finally, neuronal death caused by pneumococcal infection could be inhibited using antibodies against β-actin. The generated data potentially helps explaining mechanisms for why pneumococci frequently cause neurological sequelae.
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