Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/ijms22073303
Keywords
lipopolysaccharide; lipid A; Gram-negative pathogen; immunodeficiency
Funding
- National Institutes of Health Intramural Programs of the National Institute for Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases [1ZIAAI000155, 1ZIAAI001151, 1ZICDK015500]
- US Department of Energy (DOE), Office of Science, Basic Energy Sciences (BES) [DE-SC0015662]
- NIH [R24GM137782-01]
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Granulibacter bethesdensis can infect patients with chronic granulomatous disease by its unique lipopolysaccharide structure characterized by strong acid resistance and low proinflammatory potency, potentially contributing to immune evasion and resistance to antimicrobial peptides.
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 alpha-Manp-(1 -> 4)-beta-GlcpN3N-(1 -> 6)-alpha-GlcpN-(11)-alpha-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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