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Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..ORCID iD: 0000-0002-4381-5037
Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England..
Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England..
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
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2019 (English)In: Nature Microbiology, E-ISSN 2058-5276, Vol. 4, no 1, p. 62-70Article in journal (Refereed) Published
Abstract [en]

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-gamma(low), interleukin-4(high) 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 4, no 1, p. 62-70
National Category
Microbiology
Identifiers
URN: urn:nbn:se:kth:diva-240700DOI: 10.1038/s41564-018-0280-xISI: 000453056100011PubMedID: 30420782Scopus ID: 2-s2.0-85056488264OAI: oai:DiVA.org:kth-240700DiVA, id: diva2:1277342
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation
Note

QC 20190110

Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved

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