Granulibacter bethesdensis, a Pathogen from Patients with Chronic Granulomatous Disease, Produces a Penta-Acylated Hypostimulatory Glycero-D-talo-oct-2-ulosonic Acid–Lipid A Glycolipid (Ko-Lipid A)

Abstract

Granulibacter bethesdensis can infect patients with chronic granulomatous disease, an immunodeficiency caused by reduced phagocyte NADPH oxidase function. Intact G. bethesdensis (Gb) is hypostimulatory compared to Escherichia coli, i.e., cytokine production in human blood requires 10–100 times more G. bethesdensis CFU/mL than E. coli. To better understand the pathogenicity of G. bethesdensis, we isolated its lipopolysaccharide (GbLPS) and characterized its lipid A. Unlike with typical Enterobacteriaceae, the release of presumptive Gb lipid A from its LPS required a strong acid. NMR and mass spectrometry demonstrated that the carbohydrate portion of the isolated glycolipid consists of α-Manp-(1→4)-β-GlcpN3N-(1→6)-α-GlcpN-(1⇿1)-α-GlcpA tetra-saccharide substituted with five acyl chains: the amide-linked N-3′ 14:0(3-OH), N-2′ 16:0(3-O16:0), and N-2 18:0(3-OH) and the ester-linked O-3 14:0(3-OH) and 16:0. The identification of glycero-d-talo-oct-2-ulosonic acid (Ko) as the first constituent of the core region of the LPS that is covalently attached to GlcpN3N of the lipid backbone may account for the acid resistance of GbLPS. In addition, the presence of Ko and only five acyl chains may explain the >10-fold lower proinflammatory potency of GbKo–lipidA compared to E. coli lipid A, as measured by cytokine induction in human blood. These unusual structural properties of the G.bethesdensis Ko–lipid A glycolipid likely contribute to immune evasion during pathogenesis and resistance to antimicrobial peptides.

Chemical Synthesis of Acetobacter pasteurianus Lipid A with a Unique Tetrasaccharide Backbone and Evaluation of Its Immunological Functions

“…Our synthetic strategy for ApLA 1 – 3 employed a tetrasaccharide scaffold decorated with a set of common orthogonal protecting groups for regioselective acylation in a divergent route. Notably, this strategy can also be useful for the synthesis of similar lipid As containing the same tetrasaccharide backbone, such as Granulibacter bethesdensis lipid A, [44] a pathogen associated with chronic granulomatous disease (CGD). Furthermore, we developed a new strategy for the construction of a 2‐trehalosamine skeleton using stereoselective 1,1′‐α,α‐glycosylation with a borinic acid catalyst, achieving an excellent yield.…”

First Report on Truffle-Inhabiting Fungi and Metagenomic Communities of Tuber Aestivum Collected in Russia

“…The potential importance of these genera of prokaryotic and eukaryotic organisms is presented in Table 5. The diversity of prokaryotic (Dahal et al 2021;Rosenberg et al 2014;Zafar and Saier 2021;Araújo et al 2021;Ke et al 2021;Muszyński et al 2021;Evangelista et al 2022;Riahi et al 2022) and eukaryotic (Litvinov 2013;Mesanza et al 2021;Vohník et al 2022;Ianiri et al 2022;Lin et al 2022) organisms and the high number of pathogenic species in the fruiting bodies of truffles indicate the complexity of the symbiotic interactions that can be observed and studied in the truffle model. Many prokaryotic and eukaryotic organisms mentioned here might influence truffles and help them form effective mycorrhizae with trees.…”

Functional neutrophil disorders: Chronic granulomatous disease and beyond

“…European strains of Granulibacter have been more severe in presentation 34 . Granulibacter requires special culture media, such as charcoal yeast extract and can be identified by 16S sequencing 30,35 . In some instances, after parenteral therapy with ceftriaxone, extended therapy with cefdinir has been effective as this can be a difficult organism to eradicate.…”