The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells.

Autor:	Serra S; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Iannotti V; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Ferrante M; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Tofiño-Vian M; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Baxendale J; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Silberberg G; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden., Kohler TP; Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany., Hammerschmidt S; Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, Greifswald, Germany., Ulijasz AT; Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA., Iovino F; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Mar 27; Vol. 27 (4), pp. 109583. Date of Electronic Publication: 2024 Mar 27 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.109583
Abstrakt:	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. Competing Interests: The authors declare no competing interests. (© 2024 The Authors.)
Databáze:	MEDLINE
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