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) |
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| Authors: | Artur Muszyń ski,Kol A. Zarember,Christian Heiss,Joseph Shiloach,Lars J. Berg,John Audley,Arina Kozyr,David E. Greenberg,Steven M. Holland,Harry L. Malech,Parastoo Azadi,Russell W. Carlson,John I. Gallin |
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| Affiliation: | 1.Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA; (C.H.); (P.A.); (R.W.C.);2.Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; (K.A.Z.); (L.J.B.); (J.A.); (A.K.); (D.E.G.); (S.M.H.); (H.L.M.);3.Biotechnology Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA; |
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| 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. |
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| Keywords: | lipopolysaccharide lipid A Gram-negative pathogen immunodeficiency |
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