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bioRxiv · 10.1101/2020.08.20.258681

Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin

Tabusi, M.·Thorsdottir, S.·Lysandrou, M.·Narciso, A. R.·Minoia, M.·Henriques-Normark, B.·Iovino, F.
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Abstract

Neuronal damage is a major consequence of bacterial meningitis, but little is known about mechanisms that lead to neuronal 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 and co-immunoprecipitation assays, we showed that pneumococci interact with the cytoskeleton protein {beta}-actin through the pilus-1 adhesin RrgA and the cytotoxin pneumolysin (Ply), thereby promoting adhesion and uptake into neurons and neuronal death. Using our bacteremia-derived meningitis mouse model, we observed that RrgA- and Ply-expressing pneumococci co-localize with neuronal {beta}-actin. We found that pneumococcal-infected neurons show increased intracellular Ca2+ levels depending on RrgA and mainly Ply which likely cause actin cytoskeleton disassembly leading to neuronal damage. Finally, neuronal death caused by pneumococcal infection could be inhibited using antibody against {beta}-actin.

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Tabusi, M., Thorsdottir, S., Lysandrou, M., Narciso, A. R., Minoia, M., Henriques-Normark, B., Iovino, F.. 2020-08-20. Neuronal death in pneumococcal meningitis is triggered by pneumolysin and pilus-1 interactions with β-actin. https://doi.org/10.1101/2020.08.20.258681

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