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

Streptococcus pneumoniae (the pneumococcus) is a major cause of mortality and morbidity globally, and the leading cause of death in under-five year olds. 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, with binding to a host cell receptor not previously demonstrated. However, here we discovered a receptor for PLY, whereby pro-inflammatory cytokine responses and TLR signaling are inhibited upon PLY binding to the Mannose-Receptor C type 1 (MRC-1) in human dendritic cells (DCs) and murine alveolar macrophages, along with upregulation of the cytokine suppressor SOCS1. Moreover, PLY-MRC-1 interaction mediates pneumococcal internalization into non-lysosomal compartments and polarizes naive T cells into an IFN-γ(low), IL-4(high) and FoxP3(+) immunoregulatory phenotype. In mice, PLY-expressing pneumococci co-localize with MRC-1 in alveolar macrophages, and induce lower pro-inflammatory cytokine responses and reduced neutrophil infiltration, compared to a PLY-mutant. In vivo, MRC-1-inhibition using blocking antibodies or MRC-1 deficient mice, show reduced bacterial loads in the airways. In conclusion, we show that pneumococci use PLY-MRC-1 interactions to downregulate inflammation and enhance bacterial survival in the airways. This has important implications for future vaccine design.