Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen

EMBO J. 2017 Mar 15;36(6):751-760. doi: 10.15252/embj.201695581. Epub 2017 Jan 18.

Abstract

Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen Escherichia coli K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing. In contrast, engagement of the activating counterpart Siglec-16 increases elimination of bacteria. Since mice do not have paired Siglec receptors, we generated a model by replacing the inhibitory domain of mouse Siglec-E with the activating module of Siglec-16. Siglec-E16 enhanced proinflammatory cytokine expression and bacterial killing in macrophages and boosted protection against intravenous bacterial challenge. These data elucidate uniquely human interactions of a pathogen with Siglecs and support the long-standing hypothesis that activating counterparts of paired immune receptors evolved as a response to pathogen molecular mimicry of host ligands for inhibitory receptors.

Keywords: Escherichia coli K1; Siglec; molecular mimicry; paired receptors; polysialic acid.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Escherichia coli / immunology
  • Escherichia coli / pathogenicity
  • Escherichia coli Infections / immunology
  • Escherichia coli Infections / pathology
  • Humans
  • Immune Evasion
  • Inflammation / pathology*
  • Lectins / metabolism*
  • Macrophages / immunology
  • Macrophages / microbiology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Microbial Viability
  • Sialic Acid Binding Immunoglobulin-like Lectins / metabolism*
  • Sialic Acids / metabolism*

Substances

  • Cytokines
  • Lectins
  • Membrane Proteins
  • SIGLEC11 protein, human
  • SIGLEC16 protein, human
  • Sialic Acid Binding Immunoglobulin-like Lectins
  • Sialic Acids
  • polysialic acid