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Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia

Ercoli, Giuseppe; Fernandes, Vitor E.; Chung, Wen Y.; Wanford, Joseph J.; Thomson, Sarah; Bayliss, Christopher D.; Straatman, Kornelis; Crocker, Paul R.; Dennison, Ashley; Martinez-Pomares, Luisa; Andrew, Peter W.; Moxon, E. Richard; Oggioni, Marco R.

Authors

Giuseppe Ercoli

Vitor E. Fernandes

Wen Y. Chung

Joseph J. Wanford

Sarah Thomson

Christopher D. Bayliss

Kornelis Straatman

Paul R. Crocker

Ashley Dennison

Peter W. Andrew

E. Richard Moxon

Marco R. Oggioni



Abstract

Bacterial septicaemia is a major cause of mortality, but its pathogenesis remains poorly understood. In experimental pneumococcal murine intravenous infection, an initial reduction of bacteria in the blood is followed hours later by a fatal septicaemia. These events represent a population-bottleneck driven by efficient clearance of pneumococci by splenic macrophages and neutrophils, but as we show here, accompanied by occasional intracellular replication of bacteria that are taken up by a sub-set of CD169-positive splenic macrophages. In this model, proliferation of these sequestered bacteria provides a reservoir for dissemination of pneumococci into the bloodstream, as demonstrated by its prevention using an anti-CD169 mAb treatment. Intracellular replication of pneumococci within CD169+ plenic macrophages was also observed in an ex vivo porcine spleen, where the microanatomy is comparable to humans. We also showed that macrolides, that effectively penetrate macrophages, prevented septicaemia whereas beta-lactams, with inefficient intracellular penetration, failed to prevent dissemination to the blood. Our findings define a shift in our understanding of the pneumococcus from an exclusively extracellular pathogen to one with an intracellular phase. These findings open the door to the development of treatments that target this early, previously unrecognized intracellular phase of bacterial sepsis.

Journal Article Type Article
Publication Date Jun 1, 2018
Journal Nature Microbiology
Electronic ISSN 2058-5276
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 3
APA6 Citation Ercoli, G., Fernandes, V. E., Chung, W. Y., Wanford, J. J., Thomson, S., Bayliss, C. D., …Oggioni, M. R. (2018). Intracellular replication of Streptococcus pneumoniae inside splenic macrophages serves as a reservoir for septicaemia. Nature Microbiology, 3, https://doi.org/10.1038/s41564-018-0147-1
DOI https://doi.org/10.1038/s41564-018-0147-1
Publisher URL https://www.nature.com/articles/s41564-018-0147-1
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Ercoli Nature Microbiology 2018 final author version.pdf (1.3 Mb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf


2Ercoli Nature Microbiology 2018 supplementary final author version.pdf (914 Kb)
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