scholarly journals 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)

2021 ◽  
Vol 22 (7) ◽  
pp. 3303
Author(s):  
Artur Muszyński ◽  
Kol A. Zarember ◽  
Christian Heiss ◽  
Joseph Shiloach ◽  
Lars J. Berg ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Human Blood ◽  
Lipid A ◽  
Acid Resistance ◽  
Strong Acid ◽  
Granulomatous Disease ◽  
E Coli ◽  
Phagocyte Nadph Oxidase ◽  
Acyl Chains ◽  
Ulosonic Acid

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.

scholarly journals Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease

2016 ◽  
pp. fuw042 ◽  
Author(s):  
Helene Buvelot ◽  
Klara M. Posfay-Barbe ◽  
Patrick Linder ◽  
Jacques Schrenzel ◽  
Karl-Heinz Krause
Keyword(s):  
Staphylococcus Aureus ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Phagocyte Nadph Oxidase

scholarly journals The p47phox mouse knock-out model of chronic granulomatous disease.

1995 ◽  
Vol 182 (3) ◽  
pp. 751-758 ◽  
Author(s):  
S H Jackson ◽  
J I Gallin ◽  
S M Holland
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Critical Role ◽  
Granulomatous Inflammation ◽  
Mammalian Host ◽  
Granulomatous Disease ◽  
Knock Out ◽  
Phagocyte Nadph Oxidase ◽  
Life Threatening

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

scholarly journals Genetic Basis and Physiological Effects of Lipid A Hydroxylation in Pseudomonas aeruginosa PAO1

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 291 ◽  
Author(s):  
Alessandra Lo Sciuto ◽  
Matteo Cervoni ◽  
Roberta Stefanelli ◽  
Maria Concetta Spinnato ◽  
Alessandra Di Giamberardino ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Outer Membrane ◽  
Human Blood ◽  
Genetic Basis ◽  
Lipid A ◽  
Acyl Chain ◽  
Membrane Integrity ◽  
Physiological Role ◽  
Infection Model ◽  
Acyl Chains

Modifications of the lipid A moiety of lipopolysaccharide influence the physicochemical properties of the outer membrane of Gram-negative bacteria. Some bacteria produce lipid A with a single hydroxylated secondary acyl chain. This hydroxylation is catalyzed by the dioxygenase LpxO, and is important for resistance to cationic antimicrobial peptides (e.g., polymyxins), survival in human blood, and pathogenicity in animal models. The lipid A of the human pathogen Pseudomonas aeruginosa can be hydroxylated in both secondary acyl chains, but the genetic basis and physiological role of these hydroxylations are still unknown. Through the generation of single and double deletion mutants in the lpxO1 and lpxO2 homologs of P. aeruginosa PAO1 and lipid A analysis by mass spectrometry, we demonstrate that both LpxO1 and LpxO2 are responsible for lipid A hydroxylation, likely acting on different secondary acyl chains. Lipid A hydroxylation does not appear to affect in vitro growth, cell wall stability, and resistance to human blood or antibiotics in P. aeruginosa. In contrast, it is required for infectivity in the Galleria mellonella infection model, without relevantly affecting in vivo persistence. Overall, these findings suggest a role for lipid A hydroxylation in P. aeruginosa virulence that could not be directly related to outer membrane integrity.

scholarly journals Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Baruch Wolach ◽  
Yitshak Scharf ◽  
Ronit Gavrieli ◽  
Martin de Boer ◽  
Dirk Roos
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
X Chromosome ◽  
Clinical Symptoms ◽  
Novel Mutation ◽  
Late Presentation ◽  
Granulomatous Disease ◽  
Phagocyte Nadph Oxidase ◽  
Mucosal Cells ◽  
General Defect

Abstract Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91phox, a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG[90-92] → GGT), predicting Tyr30Arg31 → stop, Val in gp91phox, who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her X-chromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow.

scholarly journals Arginine-Agmatine Antiporter in Extreme Acid Resistance in Escherichia coli

2003 ◽  
Vol 185 (22) ◽  
pp. 6556-6561 ◽  
Author(s):  
Ram Iyer ◽  
Carole Williams ◽  
Christopher Miller
Keyword(s):  
Escherichia Coli ◽  
Acid Resistance ◽  
Strong Acid ◽  
Enteric Bacteria ◽  
Arginine Decarboxylase ◽  
Transport Protein ◽  
Gene Arrangement ◽  
Coupled Transport ◽  
E Coli ◽  
Acid Environment

ABSTRACT The process of arginine-dependent extreme acid resistance (XAR) is one of several decarboxylase-antiporter systems that protects Escherichia coli and possibly other enteric bacteria from exposure to the strong acid environment of the stomach. Arginine-dependent acid resistance depends on an intracellular proton-utilizing arginine α-decarboxylase and a membrane transport protein necessary for delivering arginine to and removing agmatine, its decarboxylation product, from the cytoplasm. The arginine system afforded significant protection to wild-type E. coli cells in our acid shock experiments. The gene coding for the transport protein is identified here as a putative membrane protein of unknown function, YjdE, which we now name adiC. Strains from which this gene is deleted fail to mount arginine-dependent XAR, and they cannot perform coupled transport of arginine and agmatine. Homologues of this gene are found in other bacteria in close proximity to homologues of the arginine decarboxylase in a gene arrangement pattern similar to that in E coli. Evidence for a lysine-dependent XAR system in E. coli is also presented. The protection by lysine, however, is milder than that by arginine.

scholarly journals Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase

2008 ◽  
Vol 30 (3) ◽  
pp. 255-271 ◽  
Author(s):  
Michela G. Schäppi ◽  
Vincent Jaquet ◽  
Dominique C. Belli ◽  
Karl-Heinz Krause
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Phagocyte Nadph Oxidase ◽  
Anti Inflammatory

scholarly journals 3-Deoxy-d-manno-oct-2-ulosonic Acid (Kdo) Transferase of Legionella pneumophila Transfers Two Kdo Residues to a Structurally Different Lipid A Precursor ofEscherichia coli

2000 ◽  
Vol 182 (16) ◽  
pp. 4654-4657 ◽  
Author(s):  
Werner Brabetz ◽  
Christiane E. Schirmer ◽  
Helmut Brade
Keyword(s):  
Escherichia Coli ◽  
Legionella Pneumophila ◽  
Lipid A ◽  
Ofescherichia Coli ◽  
Bifunctional Enzyme ◽  
E Coli ◽  
Transferase Gene ◽  
Structural Differences ◽  
Ulosonic Acid

ABSTRACT The 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) transferase gene of Legionella pneumophila was cloned and sequenced. Despite remarkable structural differences in lipid A, the gene complemented a corresponding Escherichia colimutant and was shown to encode a bifunctional enzyme which transferred 2 Kdo residues to a lipid A acceptor of E. coli.

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