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Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival

Nature Microbiology volume 4, pages 62–70 (2019)Cite this article

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Abstract

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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Fig. 1: PLY inhibits cytokine responses and inflammatory signalling in DCs by upregulating SOCS1.
Fig. 2: MRC-1 colocalizes with PLY and intracellular pneumococci in DCs.
Fig. 3: Depletion of MRC-1 abolishes PLY-induced cytokine inhibition and enhances T cell activation.
Fig. 4: MRC-1 mediates PLY-induced suppression of early inflammatory responses in vivo.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

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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Author notes

  1. These authors contributed equally: Karthik Subramanian, Daniel R. Neill.

  2. These authors jointly supervised this work: Aras Kadioglu, Birgitta Henriques-Normark.

Authors and Affiliations

  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    Karthik Subramanian, Laura Spelmink, Giorgia Dalla Libera Marchiori, Laura Plant & Birgitta Henriques-Normark

  2. Institute of Infection and Global Health, University of Liverpool, Liverpool, UK

    Daniel R. Neill, Hesham A. Malak, Shadia Khandaker, Emma Dearing, Marie Yang & Aras Kadioglu

  3. Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York, UK

    Alun Kirby

  4. Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

    Adnane Achour

  5. Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden

    Adnane Achour

  6. Division of Protein Technology, School of Biotechnology, Royal Institute of Technology (KTH), Stockholm, Sweden

    Johan Nilvebrant & Per-Åke Nygren

  7. Clinical Microbiology, Karolinska University Hospital Solna, Stockholm, Sweden

    Birgitta Henriques-Normark

  8. Lee Kong Chian School of Medicine (LKC) and Singapore Centre on Environmental Life Sciences Engineering (SCELSE), Nanyang Technological University, Singapore, Singapore

    Birgitta Henriques-Normark

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  1. Karthik Subramanian
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Contributions

K.S., D.R.N., L.S., A. Kadioglu and B.H.-N. designed the study. K.S., L.S., G.D.L.M., H.M., S.K., E.D., M.Y., D.R.N., A.A., J.N., P.-Å.N., A. Kirby and L.P. performed the experiments. K.S., L.S., D.R.N., A. Kadioglu and B.H.-N. wrote the manuscript, and the other authors contributed to the writing. All authors read and approved the final version of the manuscript.

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Correspondence to Aras Kadioglu or Birgitta Henriques-Normark.

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Subramanian, K., Neill, D.R., Malak, H.A. et al. Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. Nat Microbiol 4, 62–70 (2019). https://doi.org/10.1038/s41564-018-0280-x

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