Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/151342
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dc.contributor.authorSubramanian, Karthiken_US
dc.contributor.authorNeill, Daniel R.en_US
dc.contributor.authorMalak, Hesham A.en_US
dc.contributor.authorSpelmink, Lauraen_US
dc.contributor.authorKhandaker, Shadiaen_US
dc.contributor.authorDalla Libera Marchiori, Giorgiaen_US
dc.contributor.authorDearing, Emmaen_US
dc.contributor.authorKirby, Alunen_US
dc.contributor.authorYang, Marieen_US
dc.contributor.authorAchour, Adnaneen_US
dc.contributor.authorNilvebrant, Johanen_US
dc.contributor.authorNygren, Per-Åkeen_US
dc.contributor.authorPlant, Lauraen_US
dc.contributor.authorKadioglu, Arasen_US
dc.contributor.authorHenriques-Normark, Birgittaen_US
dc.date.accessioned2021-06-22T07:21:11Z-
dc.date.available2021-06-22T07:21:11Z-
dc.date.issued2019-
dc.identifier.citationSubramanian, 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-xen_US
dc.identifier.issn2058-5276en_US
dc.identifier.other0000-0002-4381-5037-
dc.identifier.other0000-0002-7911-8153-
dc.identifier.other0000-0001-5663-2961-
dc.identifier.other0000-0002-6104-6446-
dc.identifier.other0000-0003-4214-6991-
dc.identifier.other0000-0003-1137-6321-
dc.identifier.other0000-0002-5429-4759-
dc.identifier.urihttps://hdl.handle.net/10356/151342-
dc.description.abstractStreptococcus 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.en_US
dc.language.isoenen_US
dc.relation.ispartofNature Microbiologyen_US
dc.rights© 2018 The Author(s), under exclusive licence to Springer Nature Limited. All rights reserved.en_US
dc.subjectScience::Medicineen_US
dc.titlePneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survivalen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.contributor.researchSingapore Centre for Environmental Life Sciences and Engineering (SCELSE)en_US
dc.identifier.doi10.1038/s41564-018-0280-x-
dc.identifier.pmid30420782-
dc.identifier.scopus2-s2.0-85056488264-
dc.identifier.issue1en_US
dc.identifier.volume4en_US
dc.identifier.spage62en_US
dc.identifier.epage70en_US
dc.subject.keywordsBacterial Host Responseen_US
dc.subject.keywordsBacterial Pathogenesisen_US
item.grantfulltextnone-
item.fulltextNo Fulltext-
Appears in Collections:LKCMedicine Journal Articles

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