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Chang Y.-C.,Glycobiology Research and Training Center | Chang Y.-C.,University of California at San Diego | Nizet V.,Glycobiology Research and Training Center | Nizet V.,University of California at San Diego

Siglecs are mammalian sialic acid (Sia) recognizing immunoglobulin-like receptors expressed across the major leukocyte lineages, and function to recognize ubiquitous Sia epitopes on cell surface glycoconjugates and regulate immunological and inflammatory activities of these cells. A large subset referred to as CD33-related Siglecs are inhibitory receptors that limit leukocyte activation, and recent research has shown that the pathogen group B Streptococcus (GBS) binds to these Siglecs in Sia-and protein-dependent fashion to downregulate leukocyte bactericidal capacity. Conversely, sialoadhesin is a macrophage phagocytic receptor that engages GBS and other sialylated pathogens to promote effective phagocytosis and antigen presentation for the adaptive immune response. A variety of other important Siglec interactions with bacterial, viral and protozoan pathogens are beginning to be recognized. Siglec genes and binding specificities are rapidly evolving among primates, with key extant polymorphisms in human populations that may influence susceptibility to infection-associated disorders including chronic obstructive pulmonary disease and premature birth. This review summarizes current understanding of interactions between pathogens and Siglecs, a field of investigation that is likely to continue expanding in scope and medical importance. © 2014 The Author. Source

Tang X.X.,Howard Hughes Medical Institute | Moninger T.O.,University of Iowa | Choudhury B.,Glycobiology Research and Training Center | Varki A.,Glycobiology Research and Training Center | And 3 more authors.
Journal of Clinical Investigation

Cystic fibrosis (CF) disrupts respiratory host defenses, allowing bacterial infection, inflammation, and mucus accumulation to progressively destroy the lungs. Our previous studies revealed that mucus with abnormal behavior impaired mucociliary transport in newborn CF piglets prior to the onset of secondary manifestations. To further investigate mucus abnormalities, here we studied airway surface liquid (ASL) collected from newborn piglets and ASL on cultured airway epithelia. Fluorescence recovery after photobleaching revealed that the viscosity of CF ASL was increased relative to that of non-CF ASL. CF ASL had a reduced pH, which was necessary and sufficient for genotype-dependent viscosity differences. The increased viscosity of CF ASL was not explained by pH-independent changes in HCO3-concentration, altered glycosylation, additional pH-induced disulfide bond formation, increased percentage of nonvolatile material, or increased sulfation. Treating acidic ASL with hypertonic saline or heparin largely reversed the increased viscosity, suggesting that acidic pH influences mucin electrostatic interactions. These findings link loss of cystic fibrosis transmembrane conductance regulator-dependent alkalinization to abnormal CF ASL. In addition, we found that increasing Ca2+ concentrations elevated ASL viscosity, in part, independently of pH. The results suggest that increasing pH, reducing Ca2+ concentration, and/or altering electrostatic interactions in ASL might benefit early CF. Source

Fong J.J.,Glycobiology Research and Training Center | Sreedhara K.,Glycobiology Research and Training Center | Deng L.,Glycobiology Research and Training Center | Varki N.M.,Glycobiology Research and Training Center | And 6 more authors.
EMBO Journal

The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid-independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec-5 and Siglec-14. Hsp70 stimulation through Siglec-5 delivers an anti-inflammatory signal, while stimulation through Siglec-14 is pro-inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non-sialic acid-bearing molecule can be either a danger-associated or self-associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action. © 2015 The Authors. Source

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