Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival

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Subramanian, Karthik, Neill, DR ORCID: 0000-0002-7911-8153, Malak, Hesham, Spelmink, Laura, Khandaker, Shadia, Marchiori, Girogia, Dearing, Emma, Kirby, Alun, Yang, Marie, Achour, Adnane et al (show 5 more authors) , Nilvebrant, Johan, Nygren, Per-Ake, Plant, Laura, Kadioglu, Aras ORCID: 0000-0003-1137-6321 and Henriques-Normark, Birgitta (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). pp. 62-70.

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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.

Item Type:	Article
Uncontrolled Keywords:	bacterial host response, bacterial pathogenesis, bacterial toxins, immunopathogenesis, infection
Depositing User:	Symplectic Admin
Date Deposited:	09 Dec 2019 09:54
Last Modified:	19 Jan 2023 00:13
DOI:	10.1038/s41564-018-0280-x
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3065218

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• Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. (deposited 13 Nov 2018 11:56)
  • Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival. (deposited 09 Dec 2019 09:54) [Currently Displayed]