Discovery and characterization of sialic acid O-acetylation in group B<i>Streptococcus</i>

Lewis, Amanda L.; Nizet, Victor; Varki, Ajit

doi:10.1073/pnas.0403010101

Cited by 148 publications

(173 citation statements)

References 64 publications

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“…The sialylated GBS exopolysaccharide capsule appears to mitigate hBMEC invasion (6) and inflammatory activation (14). However, our analysis of acidreleased GBS sialic acids by 1,2-diamino-4,5-methylenedioxybenzene (DMB) derivatization and reverse-phase HPLC (15) revealed no difference in capsular sialic acid content between WT and ∆iagA mutant strains (data not shown). The hypo-invasive phenotype of a targeted deletion of the iagA gene in a capsule-negative GBS strain ( Figure 2B) further supports a role for iagA in hBMEC invasion that is independent of capsule.…”

Section: Identification Of a Gbs Gene Associated With Hbmec Invasionmentioning

confidence: 82%

Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

Doran¹,

Engelson²,

Khosravi³

et al. 2005

J. Clin. Invest.

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Group B streptococci (GBSs) are the leading cause of neonatal meningitis. GBSs enter the CNS by penetrating the blood-brain barrier (BBB), which consists of specialized human brain microvascular endothelial cells (hBMECs). To identify GBS factors required for BBB penetration, we generated random mutant libraries of a virulent strain and screened for loss of hBMEC invasion in vitro. Two independent hypo-invasive mutants possessed disruptions in the same gene, invasion associated gene (iagA), which encodes a glycosyltransferase homolog. Allelic replacement of iagA in the GBS chromosome produced a 4-fold decrease in hBMEC invasiveness. Mice challenged with the GBS ∆iagA mutant developed bacteremia comparably to WT mice, yet mortality was significantly lower (20% vs. 90%), as was the incidence of meningitis. The glycolipid diglucosyldiacylglycerol, a cell membrane anchor for lipoteichoic acid (LTA) and predicted product of the IagA glycosyltransferase, was absent in the ∆iagA mutant, which consequently shed LTA into the media. Attenuation of virulence of the ∆iagA mutant was found to be independent of TLR2-mediated signaling, but bacterial supernatants from the ∆iagA mutant containing released LTA inhibited hBMEC invasion by WT GBS. Our data suggest that LTA expression on the GBS surface plays a role in bacterial interaction with BBB endothelium and the pathogenesis of neonatal meningitis.

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Section: Identification Of a Gbs Gene Associated With Hbmec Invasionmentioning

confidence: 82%

Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

Doran¹,

Engelson²,

Khosravi³

et al. 2005

J. Clin. Invest.

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195

272

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“…Recently, we described the biochemical and genetic basis of capsular Sia O-acetylation in GBS (17,18), a modification unrecognized during earlier GBS capsule studies. The O-acetyl modification of Sias and related molecules is not unique to GBS; rather, it is characteristic of many bacterial pathogens (17, 19 -26) as well as many vertebrate cell types (27)(28)(29)(30)(31)(32).…”

Section: N-acetylneuraminic Acid (Neu5ac)mentioning

confidence: 99%

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

Lewis

Cao

Patel

et al. 2007

Journal of Biological Chemistry

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“…In GBS, the CPS is a high-molecularweight polymer composed of varying sequences of ␤-Dgalactopyranose (␤-D-Galp), ␤-D-glucopyranose (␤-D-Glcp), ␤-D-N-acetylglucosamine (␤-D-GlcpNAc), ␣-N-acetylneuraminic acid (␣-Neu5Ac), and sometimes L-rhamnopyranose. The glyceryl side chain of the Neu5Ac residues may also be Oacetylated (4). In all GBS strains identified to date, the Neu5Ac residues occur in the terminal position on the side-chain branches of the polymeric repeat unit of the CPS.…”

Section: S Treptococcus Agalactiae [Group B Streptococcus (Gbs)] Andmentioning

confidence: 99%

Understanding the bacterial polysaccharide antigenicity ofStreptococcus agalactiaeversusStreptococcus pneumoniae

Kadirvelraj

González-Outeiriño

Foley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial surface capsular polysaccharides (CPS) that are similar in carbohydrate sequence may differ markedly in immunogenicity and antigenicity. The structural origin of these phenomena is poorly understood. Such a case is presented by the Gram-positive bacteria Streptococcus agalactiae (Group B Streptococcus; GBS) type III (GBSIII) and Streptococcus pneumoniae (Pn) type 14 (Pn14), which share closely related CPS sequences. Nevertheless, antibodies (Abs) against GBSIII rarely cross-react with the CPS from Pn14. To establish the origin for the variation in CPS antigenicity, models for the immune complexes of CPS fragments from GBSIII and Pn14, with the variable fragment (Fv) of a GBS-specific mAb (mAb 1B1), are presented. The complexes are generated through a combination of comparative Ab modeling and automated ligand docking, followed by explicitly solvated 10-ns molecular dynamics simulations. The relationship between carbohydrate sequence and antigenicity is further quantified through the computation of interaction energies using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method, augmented by conformational entropy estimates. Despite the electrostatic differences between Pn14 and GBSIII CPS, analysis indicates that entropic penalties are primarily responsible for the loss of affinity of the highly flexible Pn14 CPS for mAb 1B1. The similarity of the solution conformation of the relatively rigid GBSIII CPS with that in the immune complex characterizes the previously undescribed 3D structure of the conformational epitope. The analysis provides a comprehensive interpretation for a large body of biochemical and immunological data related to Ab recognition of bacterial polysaccharides and should be applicable to other Ab-carbohydrate interactions. S treptococcus agalactiae [Group B Streptococcus (GBS)] andStreptococcus pneumoniae (Pn) are responsible for the majority of life-threatening cases of septicemia, meningitis, and pneumonia in neonates (1, 2). Gram-positive bacteria, such as GBS and Pn, are classified into serotypes according to the unique carbohydrate sequence of the bacterial surface capsular polysaccharide (CPS) and protein antigens. Serotypes vary in antigenicity, immunogenicity, virulence, and geographical distribution (3). Quantification of the structural and dynamic properties responsible for the affinity and specificity of antigenic oligosaccharide-antibody (Ab) interactions is a crucial step in furthering the understanding of the immune response to bacterial and fungal pathogens. In GBS, the CPS is a high-molecularweight polymer composed of varying sequences of ␤-D-, and sometimes L-rhamnopyranose. The glyceryl side chain of the Neu5Ac residues may also be Oacetylated (4). In all GBS strains identified to date, the Neu5Ac residues occur in the terminal position on the side-chain branches of the polymeric repeat unit of the CPS. They play an important role in defining the antigenicity and immunogenicity of the CPS (5). Variations within the CPS sequence result in the nine kno...

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Discovery and characterization of sialic acid O-acetylation in group BStreptococcus

Abstract: Streptococcus agalactiae ͉ polysaccharide capsule ͉ Neu5Ac

Cited by 148 publications

References 64 publications

Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

Blood-brain barrier invasion by group B Streptococcus depends upon proper cell-surface anchoring of lipoteichoic acid

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

Understanding the bacterial polysaccharide antigenicity ofStreptococcus agalactiaeversusStreptococcus pneumoniae

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