TY - JOUR
T1 - Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival
AU - Subramanian, Karthik
AU - Neill, Daniel R.
AU - Malak, Hesham A.
AU - Spelmink, Laura
AU - Khandaker, Shadia
AU - Dalla Libera Marchiori, Giorgia
AU - Dearing, Emma
AU - Kirby, Alun
AU - Yang, Marie
AU - Achour, Adnane
AU - Nilvebrant, Johan
AU - Nygren, Per Åke
AU - Plant, Laura
AU - Kadioglu, Aras
AU - Henriques-Normark, Birgitta
N1 - Funding Information:
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.
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056488264&partnerID=8YFLogxK
U2 - 10.1038/s41564-018-0280-x
DO - 10.1038/s41564-018-0280-x
M3 - Letter
C2 - 30420782
SN - 2058-5276
VL - 4
SP - 62
EP - 70
JO - Nature Microbiology
JF - Nature Microbiology
ER -