scholarly journals Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response

Blood ◽  
2009 ◽  
Vol 113 (14) ◽  
pp. 3333-3336 ◽  
Author(s):  
Aaron F. Carlin ◽  
Satoshi Uchiyama ◽  
Yung-Chi Chang ◽  
Amanda L. Lewis ◽  
Victor Nizet ◽  
...  
Keyword(s):  
Capsular Polysaccharide ◽  
Molecular Mimicry ◽  
Group B Streptococcus ◽  
Bacterial Pathogen ◽  
Extracellular Dna ◽  
Dependent Manner ◽  
Bacterial Survival ◽  
Amino Terminal ◽  
Group B ◽  
In Cis

Abstract Human neutrophil Siglec-9 is a lectin that recognizes sialic acids (Sias) via an amino-terminal V-set Ig domain and possesses tyrosine-based inhibitory motifs in its cytoplasmic tail. We hypothesized that Siglec-9 recognizes host Sias as “self,” including in cis interactions with Sias on the neutrophil's own surface, thereby dampening unwanted neutrophil reactivity. Here we show that neutrophils presented with immobilized multimerized Siaα2-3Galβ1-4GlcNAc units engage them in trans via Siglec-9. The sialylated capsular polysaccharide of group B Streptococcus (GBS) also presents terminal Siaα2-3Galβ1-4GlcNAc units, and similarly engages neutrophil Siglec-9, dampening neutrophil responses in a Sia- and Siglec-9–dependent manner. Reduction in the neutrophil oxidative burst, diminished formation of neutrophil extracellular DNA traps, and increased bacterial survival are also facilitated by GBS sialylated capsular polysaccharide interactions with Siglec-9. Thus, GBS can impair neutrophil defense functions by coopting a host inhibitory receptor via sialoglycan molecular mimicry, a novel mechanism of bacterial immune evasion.

scholarly journals Group B Streptococcus suppression of phagocyte functions by protein-mediated engagement of human Siglec-5

2009 ◽  
Vol 206 (8) ◽  
pp. 1691-1699 ◽  
Author(s):  
Aaron F. Carlin ◽  
Yung-Chi Chang ◽  
Thomas Areschoug ◽  
Gunnar Lindahl ◽  
Nancy Hurtado-Ziola ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Capsular Polysaccharide ◽  
Group B Streptococcus ◽  
Protein Tyrosine Phosphatases ◽  
Human Leukocyte ◽  
Bacterial Survival ◽  
Independent Manner ◽  
Lectin Receptor ◽  
Β Protein ◽  
Group B

Group B Streptococcus (GBS) is a leading cause of invasive bacterial infections in human newborns. A key GBS virulence factor is its capsular polysaccharide (CPS), displaying terminal sialic acid (Sia) residues which block deposition and activation of complement on the bacterial surface. We recently demonstrated that GBS Sia can bind human CD33-related Sia-recognizing immunoglobulin (Ig) superfamily lectins (hCD33rSiglecs), a family of inhibitory receptors expressed on the surface of leukocytes. We report the unexpected discovery that certain GBS strains may bind one such receptor, hSiglec-5, in a Sia-independent manner, via the cell wall–anchored β protein, resulting in recruitment of SHP protein tyrosine phosphatases. Using a panel of WT and mutant GBS strains together with Siglec-expressing cells and soluble Siglec-Fc chimeras, we show that GBS β protein binding to Siglec-5 functions to impair human leukocyte phagocytosis, oxidative burst, and extracellular trap production, promoting bacterial survival. We conclude that protein-mediated functional engagement of an inhibitory host lectin receptor promotes bacterial innate immune evasion.

Synthesis of Group B Streptococcus type III polysaccharide fragments for evaluation of their interactions with monoclonal antibodies

2017 ◽  
Vol 89 (7) ◽  
pp. 855-875 ◽  
Author(s):  
Vittorio Cattaneo ◽  
Filippo Carboni ◽  
Davide Oldrini ◽  
Riccardo De Ricco ◽  
Nunzio Donadio ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Sialic Acid ◽  
Capsular Polysaccharide ◽  
Group B Streptococcus ◽  
Sialic Acid Residue ◽  
Dependent Manner ◽  
Helical Structures ◽  
Type Iii ◽  
Antibody Recognition ◽  
Group B

AbstractGroup B Streptococcus type III (GBSIII) is the most relevant serotype among GBS strains causing infections and the potential of its capsular polysaccharide conjugated to a protein carrier as vaccine is well documented. Polysaccharide from GBSIII (PSIII) can form helical structures in solution where negatively charged sialic acid residues would be disposed externally providing stabilization to the helix. A peculiar high affinity to specific monoclonal antibodies (mAbs) has been reported for PSIII, and fragments of diverse size bind to mAbs in a length dependent manner. These data have been rationalized in terms of conformational epitopes that would be formed by fragments with >4 saccharidic repeating units. Saturation Transfer Difference NMR experiments have demonstrated that the sialic acid residue is not involved in antibody recognition. However the molecular basis of the interaction between PSIII and mAbs has not been fully elucidated. An important prerequisite to achieve this would be the availability of the three possible sugar sequences representing the pentasaccharide PSIII repeating unit. Herein we established a [2+3] convergent approach leading to these three pentasaccharides (1–3) with the end terminal sugar bearing a linker for possible conjugation. The PSIII fragments were coupled to the genetically detoxified diphtheria toxin CRM197 to prove by ELISA that the three pentasaccharides are recognized by polyclonal anti-PSIII serum. The presence of the branching formed by a Glc residue β-(1→6) linked to GlcNAc was proven an important motif for antibody recognition.

Childhood meningitis in the conjugate vaccine era: a prospective cohort study

2014 ◽  
Vol 100 (3) ◽  
pp. 292-294 ◽  
Author(s):  
Manish Sadarangani ◽  
Louise Willis ◽  
Seilesh Kadambari ◽  
Stuart Gormley ◽  
Zoe Young ◽  
...  
Keyword(s):  
Bacterial Meningitis ◽  
Group B Streptococcus ◽  
Bacterial Pathogen ◽  
Antibiotic Use ◽  
Viral Meningitis ◽  
Older Children ◽  
C Reactive Protein ◽  
Blood Cell Count ◽  
Reactive Protein ◽  
Group B

Bacterial conjugate vaccines have dramatically changed the epidemiology of childhood meningitis; viral causes are increasingly predominant, but the current UK epidemiology is unknown. This prospective study recruited children under 16 years of age admitted to 3 UK hospitals with suspected meningitis. 70/388 children had meningitis—13 bacterial, 26 viral and 29 with no pathogen identified. Group B Streptococcus was the most common bacterial pathogen. Infants under 3 months of age with bacterial meningitis were more likely to have a reduced Glasgow Coma Score and respiratory distress than those with viral meningitis or other infections. There were no discriminatory clinical features in older children. Cerebrospinal fluid (CSF) white blood cell count and plasma C-reactive protein at all ages, and CSF protein in infants <3 months of age, distinguished between bacterial meningitis and viral meningitis or other infections. Improved diagnosis of non-bacterial meningitis is urgently needed to reduce antibiotic use and hospital stay.

scholarly journals A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta

2013 ◽  
Vol 210 (6) ◽  
pp. 1265-1281 ◽  
Author(s):  
Christopher Whidbey ◽  
Maria Isabel Harrell ◽  
Kellie Burnside ◽  
Lisa Ngo ◽  
Alexis K. Becraft ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Amniotic Fluid ◽  
Preterm Labor ◽  
Group B Streptococcus ◽  
Dependent Manner ◽  
Microbial Infection ◽  
Amniotic Cavity ◽  
Protein Toxin ◽  
Ascending Infection ◽  
Group B

Microbial infection of the amniotic fluid is a significant cause of fetal injury, preterm birth, and newborn infections. Group B Streptococcus (GBS) is an important human bacterial pathogen associated with preterm birth, fetal injury, and neonatal mortality. Although GBS has been isolated from amniotic fluid of women in preterm labor, mechanisms of in utero infection remain unknown. Previous studies indicated that GBS are unable to invade human amniotic epithelial cells (hAECs), which represent the last barrier to the amniotic cavity and fetus. We show that GBS invades hAECs and strains lacking the hemolysin repressor CovR/S accelerate amniotic barrier failure and penetrate chorioamniotic membranes in a hemolysin-dependent manner. Clinical GBS isolates obtained from women in preterm labor are hyperhemolytic and some are associated with covR/S mutations. We demonstrate for the first time that hemolytic and cytolytic activity of GBS is due to the ornithine rhamnolipid pigment and not due to a pore-forming protein toxin. Our studies emphasize the importance of the hemolytic GBS pigment in ascending infection and fetal injury.

Synthesis of a disialylated hexasaccharide of Type VIII Group B Streptococcus capsular polysaccharide

1999 ◽  
Vol 319 (1-4) ◽  
pp. 1-16 ◽  
Author(s):  
Eva Eichler ◽  
Harold J. Jennings ◽  
Michel Gilbert ◽  
Dennis M. Whitfield
Keyword(s):  
Capsular Polysaccharide ◽  
Group B Streptococcus ◽  
Type Viii ◽  
Group B

scholarly journals NeuA Sialic Acid O-Acetylesterase Activity Modulates O-Acetylation of Capsular Polysaccharide in Group B Streptococcus

2007 ◽  
Vol 282 (38) ◽  
pp. 27562-27571 ◽  
Author(s):  
Amanda L. Lewis ◽  
Hongzhi Cao ◽  
Silpa K. Patel ◽  
Sandra Diaz ◽  
Wesley Ryan ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Capsular Polysaccharide ◽  
Group B Streptococcus ◽  
Site Directed Mutagenesis ◽  
Synthetase Activity ◽  
Bacterial Surface ◽  
Acetylneuraminic Acid ◽  
Single Polypeptide ◽  
Group B

Group B Streptococcus (GBS) is a common cause of neonatal sepsis and meningitis. A major GBS virulence determinant is its sialic acid (Sia)-capped capsular polysaccharide. Recently, we discovered the presence and genetic basis of capsular Sia O-acetylation in GBS. We now characterize a GBS Sia O-acetylesterase that modulates the degree of GBS surface O-acetylation. The GBS Sia O-acetylesterase operates cooperatively with the GBS CMP-Sia synthetase, both part of a single polypeptide encoded by the neuA gene. NeuA de-O-acetylation of free 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac2) was enhanced by CTP and Mg2+, the substrate and co-factor, respectively, of the N-terminal GBS CMP-Sia synthetase domain. In contrast, the homologous bifunctional NeuA esterase from Escherichia coli K1 did not display cofactor dependence. Further analyses showed that in vitro, GBS NeuA can operate via two alternate enzymatic pathways: de-O-acetylation of Neu5,9Ac2 followed by CMP activation of Neu5Ac or activation of Neu5,9Ac2 followed by de-O-acetylation of CMP-Neu5,9Ac2. Consistent with in vitro esterase assays, genetic deletion of GBS neuA led to accumulation of intracellular O-acetylated Sias, and overexpression of GBS NeuA reduced O-acetylation of Sias on the bacterial surface. Site-directed mutagenesis of conserved asparagine residue 301 abolished esterase activity but preserved CMP-Sia synthetase activity, as evidenced by hyper-O-acetylation of capsular polysaccharide Sias on GBS expressing only the N301A NeuA allele. These studies demonstrate a novel mechanism regulating the extent of capsular Sia O-acetylation in intact bacteria and provide a genetic strategy for manipulating GBS O-acetylation in order to explore the role of this modification in GBS pathogenesis and immunogenicity.

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