Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen |
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Authors: | Flavio Schwarz Ajit Varki Flavio Schwarz Corinna S Landig Shoib Siddiqui Ismael Secundino Joshua Olson Nissi Varki Victor Nizet Ajit Varki |
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Institution: | Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA |
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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. |
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Keywords: | Escherichia coli K1 molecular mimicry paired receptors polysialic acid Siglec |
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