Chronic Granulomatous Disease: From Lethal Pediatric Mystery to Complex Chronic Disease

Zarember, Kol A.; Soule, Benjamin P.; Gallin, John I.

doi:10.1007/978-1-60761-512-5_34

Cited by 2 publications

(2 citation statements)

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“…Among these emerging pathogens is Granulibacter bethesdensis , non-motile, catalase-positive, and oxidase-negative coccobacillus first described in 2006 [ 7 ], which, to date, has only been isolated from human patients with chronic granulomatous disease (CGD), a rare primary immunodeficiency caused by deleterious mutations in the phagocyte NADPH oxidase (NOX2). Typically, NOX2 produces the superoxide anion that, together with nitric oxide, can generate antimicrobial peroxinitrite or be used by superoxide dismutase to form antimicrobial hydrogen peroxide that acts directly on microbes or can be used by myeloperoxidase to form antimicrobial hypohalous acids (bleach) and chlorine [ 8 ]. As a consequence of reduced NOX2 function, patients with CGD suffer from frequent opportunistic and often deadly infections by Aspergillus , Staphylococcus , Burkholderia , and other microbes.…”

Section: Introductionmentioning

confidence: 99%

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)

Muszyński

Zarember

Heiß

et al. 2021

IJMS

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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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Section: Introductionmentioning

confidence: 99%

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)

Muszyński

Zarember

Heiß

et al. 2021

IJMS

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“…hronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in genes encoding p22 phox , p40 phox , p47 phox , p67 phox , and gp91 phox , components of NOX2, an NADPH-oxidase enzyme complex that produces superoxide anions (1)(2)(3). Cells from patients with CGD have decreased NOX2-dependent superoxide anion production, resulting in abnormally low phagosomal concentrations of antimicrobial H 2 O 2 and myeloperoxidase-dependent hypohalous acids (e.g., hypochlorite).…”

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confidence: 99%

Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease

Greenberg

Sturdevant²,

Marshall‐Batty

et al. 2015

Infect Immun

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e Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications. Granulibacter bethesdensis is an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in PMN from healthy subjects (normal PMN) and CGD PMN during incubation with G. bethesdensis and, simultaneously, in G. bethesdensis with normal and CGD PMN. We detected upregulation of antiapoptotic genes (e.g., XIAP and GADD45B) and downregulation of proapoptotic genes (e.g., CASP8 and APAF1) in infected PMN. Transcript and protein levels of inflammation-and immunity-related genes were also altered. Upon interaction with PMN, G. bethesdensis altered the expression of ROS resistance genes in the presence of normal but not CGD PMN. Levels of bacterial stress response genes, including the ClpB gene, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knockdown demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of Granulibacter growth in PMN included the upregulation of pyruvate dehydrogenase. Pharmacological inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to Granulibacter. This study expands knowledge of microbial pathogenesis of Granulibacter in cells from permissive (CGD) and nonpermissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen.

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Chronic Granulomatous Disease: From Lethal Pediatric Mystery to Complex Chronic Disease

Cited by 2 publications

References 335 publications

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)

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)

Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease

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