The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells
Summary: Bacterial meningitis, frequently caused by Streptococcus pneumoniae (pneumococcus), represents a substantial global health threat leading to long-term neurological disorders. This study focused on the cholesterol-binding toxin pneumolysin (PLY) released by pneumococci, specifically examinin...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224008058 |
| _version_ | 1827287935237488640 |
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| author | Simona Serra Vittorio Iannotti Margherita Ferrante Miguel Tofiño-Vian Joseph Baxendale Gilad Silberberg Thomas P. Kohler Sven Hammerschmidt Andrew T. Ulijasz Federico Iovino |
| author_facet | Simona Serra Vittorio Iannotti Margherita Ferrante Miguel Tofiño-Vian Joseph Baxendale Gilad Silberberg Thomas P. Kohler Sven Hammerschmidt Andrew T. Ulijasz Federico Iovino |
| author_sort | Simona Serra |
| collection | DOAJ |
| description | Summary: Bacterial meningitis, frequently caused by Streptococcus pneumoniae (pneumococcus), represents a substantial global health threat leading to long-term neurological disorders. This study focused on the cholesterol-binding toxin pneumolysin (PLY) released by pneumococci, specifically examining clinical isolates from patients with meningitis and comparing them to the PLY-reference S. pneumoniae strain D39. Clinical isolates exhibit enhanced PLY release, likely due to a significantly higher expression of the autolysin LytA. Notably, the same single amino acid (aa) D380 substitution in the PLY D4 domain present in all clinical isolates significantly enhances cholesterol binding, pore-forming activity, and cytotoxicity toward SH-SY5Y-derived neuronal cells. Scanning electron microscopy of human neuronal cells and patch clamp electrophysiological recordings on mouse brain slices confirm the enhanced neurotoxicity of the PLY variant carrying the single aa substitution. This study highlights how a single aa modification enormously alters PLY cytotoxic potential, emphasizing the importance of PLY as a major cause of the neurological sequelae associated with pneumococcal meningitis. |
| first_indexed | 2024-04-24T11:20:50Z |
| format | Article |
| id | doaj.art-71a669239d3543b5b0d6075aebb164bb |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-24T11:20:50Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-71a669239d3543b5b0d6075aebb164bb2024-04-11T04:41:48ZengElsevieriScience2589-00422024-04-01274109583The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cellsSimona Serra0Vittorio Iannotti1Margherita Ferrante2Miguel Tofiño-Vian3Joseph Baxendale4Gilad Silberberg5Thomas P. Kohler6Sven Hammerschmidt7Andrew T. Ulijasz8Federico Iovino9Department of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, GermanyDepartment of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, GermanyDepartment of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USADepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Corresponding authorSummary: Bacterial meningitis, frequently caused by Streptococcus pneumoniae (pneumococcus), represents a substantial global health threat leading to long-term neurological disorders. This study focused on the cholesterol-binding toxin pneumolysin (PLY) released by pneumococci, specifically examining clinical isolates from patients with meningitis and comparing them to the PLY-reference S. pneumoniae strain D39. Clinical isolates exhibit enhanced PLY release, likely due to a significantly higher expression of the autolysin LytA. Notably, the same single amino acid (aa) D380 substitution in the PLY D4 domain present in all clinical isolates significantly enhances cholesterol binding, pore-forming activity, and cytotoxicity toward SH-SY5Y-derived neuronal cells. Scanning electron microscopy of human neuronal cells and patch clamp electrophysiological recordings on mouse brain slices confirm the enhanced neurotoxicity of the PLY variant carrying the single aa substitution. This study highlights how a single aa modification enormously alters PLY cytotoxic potential, emphasizing the importance of PLY as a major cause of the neurological sequelae associated with pneumococcal meningitis.http://www.sciencedirect.com/science/article/pii/S2589004224008058Natural sciencesBiological sciencesBiochemistryNeuroscienceMolecular neuroscienceMicrobiology |
| spellingShingle | Simona Serra Vittorio Iannotti Margherita Ferrante Miguel Tofiño-Vian Joseph Baxendale Gilad Silberberg Thomas P. Kohler Sven Hammerschmidt Andrew T. Ulijasz Federico Iovino The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells iScience Natural sciences Biological sciences Biochemistry Neuroscience Molecular neuroscience Microbiology |
| title | The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells |
| title_full | The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells |
| title_fullStr | The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells |
| title_full_unstemmed | The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells |
| title_short | The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells |
| title_sort | single d380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells |
| topic | Natural sciences Biological sciences Biochemistry Neuroscience Molecular neuroscience Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224008058 |
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