Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus

Syed Raza Ali; Jerry J Fong; Aaron F Carlin; Tamara D Busch; Rebecka Linden; Takashi Angata; Thomas Areschoug; Mana Parast; Nissi Varki; Jeffrey Murray; Victor Nizet; Ajit Varki

doi:10.1084/jem.20131853

Siglec-5 and Siglec-14 are polymorphic paired receptors that modulate neutrophil and amnion signaling responses to group B Streptococcus

J Exp Med. 2014 Jun 2;211(6):1231-42. doi: 10.1084/jem.20131853. Epub 2014 May 5.

Authors

Affiliations

¹ 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.
² 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.
³ Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242.
⁴ 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.
⁵ Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
⁶ Division of Medical Microbiology, Lund University, SE-223 62 Lund, Sweden.
⁷ 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.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Amnion / immunology*
Amnion / metabolism
Amnion / microbiology
Antigens, CD / genetics
Antigens, CD / immunology*
Antigens, CD / metabolism
Antigens, Differentiation, Myelomonocytic / genetics
Antigens, Differentiation, Myelomonocytic / immunology*
Antigens, Differentiation, Myelomonocytic / metabolism
Blotting, Western
Cell Line, Tumor
Cells, Cultured
DNA-Binding Proteins / genetics
DNA-Binding Proteins / immunology
DNA-Binding Proteins / metabolism
Female
Gene Expression / drug effects
Gene Expression / immunology
Genotype
Host-Pathogen Interactions / immunology
Humans
Infant, Newborn
Lectins / genetics
Lectins / immunology*
Lectins / metabolism
Lipopolysaccharides / immunology
Lipopolysaccharides / pharmacology
Monocytes / immunology
Monocytes / metabolism
Monocytes / microbiology
Neutrophils / immunology*
Neutrophils / metabolism
Neutrophils / microbiology
Phosphorylation
Polymorphism, Genetic
Pregnancy
Proto-Oncogene Proteins c-akt / metabolism
Receptors, Cell Surface / genetics
Receptors, Cell Surface / immunology*
Receptors, Cell Surface / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / immunology
Streptococcal Infections / immunology*
Streptococcal Infections / microbiology
Streptococcus agalactiae / genetics
Streptococcus agalactiae / immunology*
Streptococcus agalactiae / physiology

Substances

Antigens, CD
Antigens, Differentiation, Myelomonocytic
DNA-Binding Proteins
Lectins
Lipopolysaccharides
Receptors, Cell Surface
SIGLEC14 protein, human
SIGLEC5 protein, human
beta protein, Streptococcus
Proto-Oncogene Proteins c-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding