Streptococcus pneumoniae (the pneumococcus) is a major cause of mortality and morbidity globally, and the leading cause of death in children under 5 years old. The pneumococcal cytolysin pneumolysin (PLY) is a major virulence determinant known to induce pore-dependent pro-inflammatory responses. These inflammatory responses are driven by PLY–host cell membrane cholesterol interactions, but binding to a host cell receptor has not been previously demonstrated. Here, we discovered a receptor for PLY, whereby pro-inflammatory cytokine responses and Toll-like receptor signalling are inhibited following PLY binding to the mannose receptor C type 1 (MRC-1) in human dendritic cells and mouse alveolar macrophages. The cytokine suppressor SOCS1 is also upregulated. Moreover, PLY–MRC-1 interactions mediate pneumococcal internalization into non-lysosomal compartments and polarize naive T cells into an interferon-γlow, interleukin-4high and FoxP3+ immunoregulatory phenotype. In mice, PLY-expressing pneumococci colocalize with MRC-1 in alveolar macrophages, induce lower pro-inflammatory cytokine responses and reduce neutrophil infiltration compared with a PLY mutant. In vivo, reduced bacterial loads occur in the airways of MRC-1-deficient mice and in mice in which MRC-1 is inhibited using blocking antibodies. In conclusion, we show that pneumococci use PLY–MRC-1 interactions to downregulate inflammation and enhance bacterial survival in the airways. These findings have important implications for future vaccine design.
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The work in Sweden was supported by grants from the Swedish Research Council, Stockholm County Council, the Swedish Foundation for Strategic Research (SSF), and the Knut and Alice Wallenberg Foundation. The work in Liverpool was supported by funding from the UK Medical Research Council (programme grant number MR/P011284/1), a Sir Henry Dale Fellowship (awarded to D.R.N.) and jointly funded by the Wellcome Trust and the Royal Society (grant number 204457/Z/16/Z), a British Commonwealth Scholarship (awarded to S.K.), a Embassy of the Kingdom of Saudi Arabia Scholarship (awarded to H.M.), and the Institute of Infection & Global Health, University of Liverpool. The authors thank the Science for Life Laboratory Mass Spectrometry Based Proteomics Facility in Uppsala for the liquid chromatography–mass spectrometry analysis.
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Pneumolysin and the bacterial capsule of Streptococcus pneumoniae cooperatively inhibit taxis and motility of microglia
Journal of Neuroinflammation (2019)