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|Title:||Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival||Authors:||Subramanian, Karthik
Neill, Daniel R.
Malak, Hesham A.
Dalla Libera Marchiori, Giorgia
|Keywords:||Science::Medicine||Issue Date:||2019||Source:||Subramanian, K., Neill, D. R., Malak, H. A., Spelmink, L., Khandaker, S., Dalla Libera Marchiori, G., Dearing, E., Kirby, A., Yang, M., Achour, A., Nilvebrant, J., Nygren, P., Plant, L., Kadioglu, A. & Henriques-Normark, B. (2019). Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. Nature Microbiology, 4(1), 62-70. https://dx.doi.org/10.1038/s41564-018-0280-x||Journal:||Nature Microbiology||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.||URI:||https://hdl.handle.net/10356/151342||ISSN:||2058-5276||DOI:||10.1038/s41564-018-0280-x||Rights:||© 2018 The Author(s), under exclusive licence to Springer Nature Limited. All rights reserved.||Fulltext Permission:||none||Fulltext Availability:||No Fulltext|
|Appears in Collections:||LKCMedicine Journal Articles|
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