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)

Artur Muszyński, 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

Research output: Contribution to journalArticlepeer-review

Abstract

Granulibacter bethesdensis can infect patients with chronic granulomatous disease, an im-munodeficiency 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.

Original languageEnglish (US)
Article number3303
JournalInternational journal of molecular sciences
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2021

Keywords

  • Gram-negative pathogen, immunodeficiency
  • Lipid A
  • Lipopolysaccharide

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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