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

K. Subramanian,D. R. Neill,H. Malak,Laura Spelmink,Shadia Khandaker,G. Dalla Libera Marchiori,Emma Dearing,A. Kirby,Marie Yang,A. Achour,J. Nilvebrant,P. Nygren,Laura Plant,A. Kadioglu,B. Henriques‐Normark

Published 2018 in 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. A Streptococcuspneumoniae toxin, pneumolysin, binds to MRC-1 on phagocytes to dampen immune responses and promote infection.

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