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

Nat Microbiol. 2019 Jan;4(1):62-70. doi: 10.1038/s41564-018-0280-x. Epub 2018 Nov 12.

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.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Load
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cell Line
  • Dendritic Cells / immunology*
  • Forkhead Transcription Factors / biosynthesis
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-4 / biosynthesis
  • Macrophages, Alveolar / immunology*
  • Membrane Glycoproteins
  • Mice
  • Neutrophil Infiltration / immunology
  • Pneumococcal Infections / pathology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Streptococcus pneumoniae / genetics
  • Streptococcus pneumoniae / pathogenicity*
  • Streptolysins / genetics
  • Streptolysins / metabolism*
  • Suppressor of Cytokine Signaling 1 Protein / biosynthesis
  • T-Lymphocytes / immunology
  • Virulence Factors

Substances

  • Bacterial Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • IFNG protein, mouse
  • MRC1 protein, human
  • Membrane Glycoproteins
  • RNA, Small Interfering
  • Receptors, Immunologic
  • Socs1 protein, mouse
  • Streptolysins
  • Suppressor of Cytokine Signaling 1 Protein
  • Virulence Factors
  • plY protein, Streptococcus pneumoniae
  • Interleukin-4
  • Interferon-gamma