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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.
Spelmink, Laura
Khandaker, Shadia
Dalla Libera Marchiori, Giorgia
Dearing, Emma
Kirby, Alun
Yang, Marie
Achour, Adnane
Nilvebrant, Johan
Nygren, Per-Åke
Plant, Laura
Kadioglu, Aras
Henriques-Normark, Birgitta
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.
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.
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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