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Paired Siglec receptors generate opposite inflammatory responses to a human‐specific pathogen
Author(s) -
Schwarz Flavio,
Landig Corinna S,
Siddiqui Shoib,
Secundino Ismael,
Olson Joshua,
Varki Nissi,
Nizet Victor,
Varki Ajit
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695581
Subject(s) - biology , siglec , receptor , pathogen , inflammation , immunology , computational biology , microbiology and biotechnology , genetics
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.