The Arginine Decarboxylase Pathways of Host and Pathogen Interact to Impact Inflammatory Pathways in the Lung

Paulson, Nick B.; Gilbertsen, Adam; Dalluge, Joseph J.; Welchlin, Cole W.; Hughes, John R.; Han, Wei; Blackwell, Timothy S.; Laguna, Theresa A.; Williams, Bryan J.

doi:10.1371/journal.pone.0111441

Cited by 12 publications

(17 citation statements)

References 37 publications

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“…CFS patients did not have an increase in plasma ADMA. Increased Arg is associated with a decreased risk of infection after operative stress (31) and is used to synthesize the antimicrobial molecule agmatine under conditions of active infection (32).…”

Section: Cholesterol and Bile Acid Synthesis Through The Lathosterol mentioning

confidence: 99%

Metabolic features of chronic fatigue syndrome

Naviaux

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

302

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More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS. We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21–67 y). Females were 52 (±2.5) y old (range, 20–67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females. We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84–100%] in males using eight metabolites and 96% (95% CI, 86–100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.

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Section: Cholesterol and Bile Acid Synthesis Through The Lathosterol mentioning

confidence: 99%

Metabolic features of chronic fatigue syndrome

Naviaux

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

302

335

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“…Arginine fermentation (ie, the ADI pathway) allows P. aeruginosa to survive under anaerobic conditions when denitrification (ie, nitrates respiration) is not induced and is associated to chronic infections, biofilm/virulence, and antibiotic resistance . Interestingly, also the ADC pathway modulates the host inflammatory response …”

Section: Discussionmentioning

confidence: 99%

“…25 Interestingly, also the ADC pathway modulates the host inflammatory response. 55 Under aerobic conditions, the presence of L-arginine (even together with ammonium) in the growth medium induces the maximal expression of the Arginine-specific ABC transporters via the ArgR transcription factor, mainly to sustain the AST pathway. 53,56 It is known that in the P. aeruginosa PA14 strain, L-arginine negatively affects swarming motility, increases biofilm formation and, to a lower extent, c-di-GMP levels as compared to glucose-supplemented medium; moreover, metabolic fluxes involving arginine catabolism are enhanced.…”

Section: Discussionmentioning

confidence: 99%

A novel bacterial l‐arginine sensor controlling c‐di‐GMP levels in Pseudomonas aeruginosa

et al. 2018

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Nutrients such as amino acids play key roles in shaping the metabolism of microorganisms in natural environments and in host-pathogen interactions. Beyond taking part to cellular metabolism and to protein synthesis, amino acids are also signaling molecules able to influence group behavior in microorganisms, such as biofilm formation. This lifestyle switch involves complex metabolic reprogramming controlled by local variation of the second messenger 3', 5'-cyclic diguanylic acid (c-di-GMP). The intracellular levels of this dinucleotide are finely tuned by the opposite activity of dedicated diguanylate cyclases (GGDEF signature) and phosphodiesterases (EAL and HD-GYP signatures), which are usually allosterically controlled by a plethora of environmental and metabolic clues. Among the genes putatively involved in controlling c-di-GMP levels in P. aeruginosa, we found that the multidomain transmembrane protein PA0575, bearing the tandem signature GGDEF-EAL, is an l-arginine sensor able to hydrolyse c-di-GMP. Here, we investigate the basis of arginine recognition by integrating bioinformatics, molecular biophysics and microbiology. Although the role of nutrients such as l-arginine in controlling the cellular fate in P. aeruginosa (including biofilm, pathogenicity and virulence) is already well established, we identified the first l-arginine sensor able to link environment sensing, c-di-GMP signaling and biofilm formation in this bacterium.

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“…Recently, direct measurements of CF sputum have revealed elevated concentrations (>10µM) of agmatine, a pre-polyamine intermediate metabolite of the arginine decarboxylase pathway (Fig. 1)(26). P. aeruginosa isolates derived from CF subjects have also been found to accumulate this metabolite in vitro , though the genetic basis of this phenotype has not yet been determined (26).…”

Section: Introductionmentioning

confidence: 99%

“…1)(26). P. aeruginosa isolates derived from CF subjects have also been found to accumulate this metabolite in vitro , though the genetic basis of this phenotype has not yet been determined (26). Previous studies have reported elevated concentrations of the polyamines spermidine and putrescine (that are derived from agmatine) in CF sputum and bronchoalveolar lavage fluid (27,28).…”

Section: Introductionmentioning

confidence: 99%