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EMBO J. 2017 Jan 18. pii: e201695581. doi: 10.15252/embj.201695581. [Epub ahead of print]

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

Schwarz F1,2,3, Landig CS1,2,3, Siddiqui S1,2,3, Secundino I1,4, Olson J4, Varki N1,5, Nizet V6,4,7, Varki A6,2,3.

Author information

  • 1Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
  • 2Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 3Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 4Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  • 5Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
  • 6Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA vnizet@ucsd.edu a1varki@ucsd.edu.
  • 7Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.

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

PMID:
28100677
DOI:
10.15252/embj.201695581
[PubMed - as supplied by publisher]
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