title: Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo.
abstract: Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-κB and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection.
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, United States of America ; Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Federico C
authors.initials: FC
authors.lastname: Beasley
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Tung
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Jiquan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, United States of America ; Department of Medicine, University of California, San Diego, La Jolla, California, United States of America ; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, United States of America ; Department of Pediatrics, University of California, San Diego, La Jolla, California, United States of America ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, United States of America ; Rady Children's Hospital, San Diego, California, United States of America.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018716:Molecular Mimicry / Q000276:immunology*; D019158:N-Acetylneuraminic Acid / Q000235:genetics / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013292:Streptococcus agalactiae / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; C422908:Siglece protein, mouse; D019158:N-Acetylneuraminic Acid