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

Flavio Schwarz, Corinna S Landig, Shoib Siddiqui, Ismael Secundino, Joshua Olson, Nissi Varki, Victor Nizet, Ajit Varki

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


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 languageEnglish
Pages (from-to)751-760
Number of pages10
JournalEMBO Journal
Issue number6
Early online date18 Jan 2017
Publication statusPublished - 15 Mar 2017


  • 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


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