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.
Original language | English |
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Pages (from-to) | 751-760 |
Number of pages | 10 |
Journal | EMBO Journal |
Volume | 36 |
Issue number | 6 |
Early online date | 18 Jan 2017 |
DOIs | |
Publication status | Published - 15 Mar 2017 |
Keywords
- Animals
- Cytokines/metabolism
- Escherichia coli/immunology
- Escherichia coli Infections/immunology
- Humans
- Immune Evasion
- Inflammation/pathology
- Lectins/metabolism
- Macrophages/immunology
- Membrane Proteins/metabolism
- Mice
- Mice, Transgenic
- Microbial Viability
- Sialic Acid Binding Immunoglobulin-like Lectins/metabolism
- Sialic Acids/metabolism