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Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines.

ABSTRACT: The surface of cells is coated with a dense layer of glycans, known as the cell glycocalyx. The complex glycans in the glycocalyx are involved in various biological events, such as bacterial pathogenesis, protection of bacteria from environmental stresses, etc. Polysaccharides on the bacterial cell surface are highly conserved and accessible molecules, and thus they are excellent immunological targets. Consequently, bacterial polysaccharides and their repeating units have been extensively studied as antigens for the development of antibacterial vaccines. This Review surveys the recent developments in the synthetic and immunological investigations of bacterial polysaccharide repeating unit-based conjugate vaccines against several human pathogenic bacteria. The major challenges associated with the development of functional carbohydrate-based antibacterial conjugate vaccines are also considered.

SUBMITTER: Rohokale R

PROVIDER: S-EPMC9930202 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines.

Rohokale Rajendra R Guo Zhongwu Z

ACS infectious diseases 20230127 2

The surface of cells is coated with a dense layer of glycans, known as the cell glycocalyx. The complex glycans in the glycocalyx are involved in various biological events, such as bacterial pathogenesis, protection of bacteria from environmental stresses, etc. Polysaccharides on the bacterial cell surface are highly conserved and accessible molecules, and thus they are excellent immunological targets. Consequently, bacterial polysaccharides and their repeating units have been extensively studie ...[more]

PMID: 36706246

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Project description:Polysaccharides are essential and immunologically relevant components of bacterial cell walls. These biomolecules can be found covalently attached to lipids (e.g., O-polysaccharide (PS) contains undecaprenyl and lipopolysaccharide (LPS) contains lipid A) or noncovalently associated with cell wells (e.g., capsular PS (CPS)). Although extensive genetic studies have indicated that the Wzy-dependent biosynthetic pathway is primarily responsible for producing such polysaccharides, in vitro biochemical studies are needed to determine, for example, which gene product is responsible for catalyzing each step in the pathway, and to reveal molecular details about the Wzx translocase, Wzy polymerase and O-PS chain-length determinant. Many of these biochemical studies require access to a structurally well-defined PS repeating unit undecaprenyl pyrophosphate (RU-PP-Und), the key building block in this pathway. We describe herein the chemoenzymatic synthesis of Escherichia coli (serotype O157) RU-PP-Und. This involves (i) chemical synthesis of precursor N-acetyl-D-galactosamine (GalNAc)-PP-Und (2 weeks) and (ii) enzymatic extension of the precursor to produce RU-PP-Und (2 weeks). Undecaprenyl phosphate and peracetylated GalNAc-1-phosphate are prepared from commercially available undecaprenol and peracetylated GalNAc. The chemical coupling of these two products, followed by structural confirmation (mass spectrometry and NMR) and deprotection, generates GalNAc-PP-Und. This compound is then sequentially modified by enzymes in the E. coli serotype O157 (E. coli O157) O-PS biosynthetic pathway. Three glycosyltransferases (GTs) are involved (WbdN, WbdO and WbdP) and they transfer glucose (Glc), L-fucose (L-Fuc) and N-acetylperosamine (PerNAc) onto GalNAc-PP-Und to form the intact RU-PP-Und in a stepwise manner. Final compounds and intermediates are confirmed by mass spectrometry. The procedure can be adapted to the synthesis of analogs with different PS or lipid moieties.

Project description:BackgroundNetherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency.MethodsVaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls.ResultsNone of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls.ConclusionsVaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.

Dataset Information

Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines.

Publications

Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines.

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