title: Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen.
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 pathogenEscherichia coliK1 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.
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.|Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Flavio
authors.initials: F
authors.lastname: Schwarz
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.|Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Corinna S
authors.initials: CS
authors.lastname: Landig
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.|Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Shoib
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.|Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Secundino
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.|Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA vnizet@ucsd.edu a1varki@ucsd.edu.|Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.|Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Victor
authors.identifier: 0000-0003-3847-0422
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA vnizet@ucsd.edu a1varki@ucsd.edu.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.|Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ajit
authors.identifier: 0000-0002-2206-975X
authors.initials: A
authors.lastname: Varki
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology / Q000473:pathology; D006801:Humans; D057131:Immune Evasion; D007249:Inflammation / Q000473:pathology*; D037102:Lectins / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050296:Microbial Viability; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism*; D012794:Sialic Acids / Q000378:metabolism*
chemical_list: D016207:Cytokines; D037102:Lectins; D008565:Membrane Proteins; C464442:SIGLEC11 protein, human; C000621136:SIGLEC16 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D012794:Sialic Acids; C021319:polysialic acid
keywords: Escherichia coli K1; Siglec; molecular mimicry; paired receptors; polysialic acid