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.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding authors upon reasonable request.
Black, R. E. et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 375, 1969–1987 (2010).
Berry, A. M., Yother, J., Briles, D. E., Hansman, D. & Paton, J. C. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57, 2037–2042 (1989).
Hirst, R. A. et al. Streptococcus pneumoniae deficient in pneumolysin or autolysin has reduced virulence in meningitis. J. Infect. Dis. 197, 744–751 (2008).
Zafar, M. A., Wang, Y., Hamaguchi, S. & Weiser, J. N. Host-to-host transmission of Streptococcus pneumoniae is driven by its inflammatory toxin, pneumolysin. Cell Host Microbe 21, 73–83 (2017).
Paton, J. C., Rowan-Kelly, B. & Ferrante, A. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43, 1085–1087 (1984).
Iliev, A. I., Djannatian, J. R., Nau, R., Mitchell, T. J. & Wouters, F. S. Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin. Proc. Natl Acad. Sci. USA 104, 2897–2902 (2007).
McNeela, E. A. et al. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog. 6, e1001191 (2010).
Price, K. E. & Camilli, A. Pneumolysin localizes to the cell wall of Streptococcus pneumoniae. J. Bacteriol. 191, 2163–2168 (2009).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Kang, P. B. et al. The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J. Exp. Med. 202, 987–999 (2005).
Taylor, P. R., Gordon, S. & Martinez-Pomares, L. The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol. 26, 104–110 (2005).
Zamze, S. et al. Recognition of bacterial capsular polysaccharides and lipopolysaccharides by the macrophage mannose receptor. J. Biol. Chem. 277, 41613–41623 (2002).
McGreal, E. P. et al. The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology 16, 422–430 (2006).
Macedo-Ramos, H. et al. Evidence of involvement of the mannose receptor in the internalization of Streptococcus pneumoniae by Schwann cells. BMC Microbiol. 14, 211 (2014).
Macedo-Ramos, H. et al. Olfactory ensheathing cells as putative host cells for Streptococcus pneumoniae: evidence of bacterial invasion via mannose receptor-mediated endocytosis. Neurosci. Res. 69, 308–313 (2011).
Kadioglu, A., Weiser, J. N., Paton, J. C. & Andrew, P. W. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat. Rev. Microbiol. 6, 288–301 (2008).
Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7, 454–465 (2007).
Yasukawa, H., Sasaki, A. & Yoshimura, A. Negative regulation of cytokine signaling pathways. Annu. Rev. Immunol. 18, 143–164 (2000).
Chieppa, M. et al. Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program. J. Immunol. 171, 4552–4560 (2003).
Paton, J. C. et al. Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide. Infect. Immun. 59, 2297–2304 (1991).
Guilliams, M., Bruhns, P., Saeys, Y., Hammad, H. & Lambrecht, B. N. The function of Fcγ receptors in dendritic cells and macrophages. Nat. Rev. Immunol. 14, 94–108 (2014).
Littmann, M. et al. Streptococcus pneumoniae evades human dendritic cell surveillance by pneumolysin expression. EMBO Mol. Med. 1, 211–222 (2009).
Rajaram, M. V. S. et al. M. tuberculosis-initiated human mannose receptor signaling regulates macrophage recognition and vesicle trafficking by FcRγ-chain, Grb2, and SHP-1.Cell Rep. 21, 126–140 (2017).
Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).
Schuette, V. et al. Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4. Proc. Natl Acad. Sci. USA 113, 10649–10654 (2016).
Neill, D. R. et al. Density and duration of pneumococcal carriage is maintained by transforming growth factor β1 and T regulatory cells. Am. J. Respir. Crit. Care Med. 189, 1250–1259 (2014).
Dorrington, M. G. et al. MARCO is required for TLR2- and Nod2-mediated responses to Streptococcus pneumoniae and clearance of pneumococcal colonization in the murine nasopharynx. J. Immunol. 190, 250–258 (2013).
Shak, J. R. et al. Novel role for the Streptococcus pneumoniae toxin pneumolysin in the assembly of biofilms. mBio 4, e00655-13 (2013).
McKenzie, E. J. et al. Mannose receptor expression and function define a new population of murine dendritic cells. J. Immunol. 178, 4975–4983 (2007).
Martinez-Pomares, L. et al. Carbohydrate-independent recognition of collagens by the macrophage mannose receptor. Eur. J. Immunol. 36, 1074–1082 (2006).
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.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Hypervirulent pneumococcal serotype 1 harbours two pneumolysin variants with differential haemolytic activity
Scientific Reports (2020)
Nature Communications (2020)
Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges
Acta Neuropathologica (2020)
Pneumolysin and the bacterial capsule of Streptococcus pneumoniae cooperatively inhibit taxis and motility of microglia
Journal of Neuroinflammation (2019)