title: Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus.
abstract: Group B Streptococcus (GBS) causes invasive infections in human newborns. We recently showed that the GBS β-protein attenuates innate immune responses by binding to sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5), an inhibitory receptor on phagocytes. Interestingly, neutrophils and monocytes also express Siglec-14, which has a ligand-binding domain almost identical to Siglec-5 but signals via an activating motif, raising the possibility that these are paired Siglec receptors that balance immune responses to pathogens. Here we show that β-protein-expressing GBS binds to both Siglec-5 and Siglec-14 on neutrophils and that the latter engagement counteracts pathogen-induced host immune suppression by activating p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways. Siglec-14 is absent from some humans because of a SIGLEC14-null polymorphism, and homozygous SIGLEC14-null neutrophils are more susceptible to GBS immune subversion. Finally, we report an unexpected human-specific expression of Siglec-5 and Siglec-14 on amniotic epithelium, the site of initial contact of invading GBS with the fetus. GBS amnion immune activation was likewise influenced by the SIGLEC14-null polymorphism. We provide initial evidence that the polymorphism could influence the risk of prematurity among human fetuses of mothers colonized with GBS. This first functionally proven example of a paired receptor system in the Siglec family has multiple implications for regulation of host immunity.
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Syed Raza
authors.initials: SR
authors.lastname: Ali
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Fong
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Carlin
authors.affiliation: Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242.
authors.forename: Tamara D
authors.initials: TD
authors.lastname: Busch
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Rebecka
authors.initials: R
authors.lastname: Linden
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.affiliation: Division of Medical Microbiology, Lund University, SE-223 62 Lund, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Areschoug
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Mana
authors.initials: M
authors.lastname: Parast
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.affiliation: Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Murray
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093 a1varki@ucsd.edu vnizet@ucsd.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093Glycobiology Research and Training Center, Department of Cellular and Molecular Medicine, Department of Pediatrics, Department of Pathology, Department of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093 a1varki@ucsd.edu vnizet@ucsd.edu.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
mesh_terms: D000328:Adult; D000650:Amnion / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005838:Genotype; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D037102:Lectins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology; D013292:Streptococcus agalactiae / Q000235:genetics / Q000276:immunology* / Q000502:physiology
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D004268:DNA-Binding Proteins; D037102:Lectins; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; C514213:SIGLEC14 protein, human; C114531:SIGLEC5 protein, human; C082525:beta protein, Streptococcus; D051057:Proto-Oncogene Proteins c-akt