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Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin
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 sequel...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990213/ https://www.ncbi.nlm.nih.gov/pubmed/33760879 http://dx.doi.org/10.1371/journal.ppat.1009432 |
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author | Tabusi, Mahebali Thorsdottir, Sigrun Lysandrou, Maria Narciso, Ana Rita Minoia, Melania Srambickal, Chinmaya Venugopal Widengren, Jerker Henriques-Normark, Birgitta Iovino, Federico |
author_facet | Tabusi, Mahebali Thorsdottir, Sigrun Lysandrou, Maria Narciso, Ana Rita Minoia, Melania Srambickal, Chinmaya Venugopal Widengren, Jerker Henriques-Normark, Birgitta Iovino, Federico |
author_sort | Tabusi, Mahebali |
collection | PubMed |
description | 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 Ca(2+) 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. |
format | Online Article Text |
id | pubmed-7990213 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-79902132021-04-05 Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin Tabusi, Mahebali Thorsdottir, Sigrun Lysandrou, Maria Narciso, Ana Rita Minoia, Melania Srambickal, Chinmaya Venugopal Widengren, Jerker Henriques-Normark, Birgitta Iovino, Federico PLoS Pathog Research Article 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 Ca(2+) 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. Public Library of Science 2021-03-24 /pmc/articles/PMC7990213/ /pubmed/33760879 http://dx.doi.org/10.1371/journal.ppat.1009432 Text en © 2021 Tabusi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Tabusi, Mahebali Thorsdottir, Sigrun Lysandrou, Maria Narciso, Ana Rita Minoia, Melania Srambickal, Chinmaya Venugopal Widengren, Jerker Henriques-Normark, Birgitta Iovino, Federico Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin |
title | Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin |
title_full | Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin |
title_fullStr | Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin |
title_full_unstemmed | Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin |
title_short | Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with β-actin |
title_sort | neuronal death in pneumococcal meningitis is triggered by pneumolysin and rrga interactions with β-actin |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990213/ https://www.ncbi.nlm.nih.gov/pubmed/33760879 http://dx.doi.org/10.1371/journal.ppat.1009432 |
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