Treatment of MRSA Infections in an African-American Male with G6PD Deficiency

Paek, David; Nadkarni, Milan; Singla, Manav

doi:10.1016/j.jemermed.2007.10.049

Cited by 4 publications

(2 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic metabolic abnormality caused by deficiency of the enzyme G6PD and the most common human enzymopathy, affecting upward of an estimated 400 million people worldwide ( 51 ). G6PD deficiency has been linked to increased susceptibility to infection and absent NETosis ( 52 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

Glucose-6-Phosphate Acts as an Extracellular Signal of SagS To Modulate Pseudomonas aeruginosa c-di-GMP Levels, Attachment, and Biofilm Formation

Park

Dingemans

Gowett

et al. 2021

mSphere

View full text Add to dashboard Cite

In Pseudomonas aeruginosa, the orphan two-component sensor SagS contributes both to transition to biofilm formation and to biofilm cells gaining their heightened tolerance to antimicrobials. However, little is known about the identity of the signals or conditions sensed by SagS to induce the switch to the sessile, drug-tolerant mode of growth. Using a modified Biolog phenotype assay to screen for compounds that modulate attachment in a SagS-dependent manner, we identified glucose-6-phosphate to enhance attachment in a manner dependent on the glucose-6-phosphate concentration and SagS. The stimulatory effect was not limited to the attachment since glucose-6-phosphate likewise enhanced biofilm formation and also enhanced the expression of select biofilm marker genes. Moreover, exposure to glucose-6-phosphate coincided with decreased swarming motility but increased cellular cyclic-di-GMP (c-di-GMP) levels in biofilms. No such response was noted for compounds modulating attachment and biofilm formation in a manner independent of SagS. Modulation of c-di-GMP in response to glucose-6-phosphate was due to the diguanylate cyclase NicD, with NicD also being required for enhanced biofilm formation. The latter was independent of the sensory domain of NicD but dependent on NicD activity, SagS, and the interaction between NicD and SagS. Our findings indicate that glucose-6-phosphate likely mimics a signal or conditions sensed by SagS to activate its motile-sessile switch function. In addition, our findings provide new insight into the interfaces between the ligand-mediated two-component system signaling pathway and c-di-GMP levels. IMPORTANCE Pathogens sense and respond to signals and cues present in their environment, including host-derived small molecules to modulate the expression of their virulence repertoire. Here, we demonstrate that the opportunistic pathogen Pseudomonas aeruginosa responds to glucose-6-phosphate. Since glucose-6-phosphate is primarily made available due to cell lysis, it is likely that glucose-6-phosphate represents a cross-kingdom cell-to-cell signal that enables P. aeruginosa to adapt to the (nutrient-poor) host environment by enhancing biofilm formation, cyclic-di-GMP, and the expression of genes linked to biofilm formation in a concentration- and SagS-dependent manner.

show abstract

Section: Discussionmentioning

confidence: 99%

Glucose-6-Phosphate Acts as an Extracellular Signal of SagS To Modulate Pseudomonas aeruginosa c-di-GMP Levels, Attachment, and Biofilm Formation

Park

Dingemans

Gowett

et al. 2021

mSphere

View full text Add to dashboard Cite

show abstract

“…Wilmanski and colleagues demonstrated that hyperinflammation (increasing cytokine levels) caused by acute endotoxemia (induced by the injection of Escherichia coli lipopolysaccharide) resulted in increased mortality in G6PDdeficient mice [15]. Several studies also indicated that G6PD deficiency in leukocytes can result in chronic granulomatous disease (CGD) and possibly alter the host defense mechanisms for bacterial infections [16][17][18]. Thus far, the impact of bacterial infection on patients with G6PD deficiency has been found to primarily affect the blood cells, leading to hemolysis or immune weakness based upon the above studies.…”

Section: Introductionmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Epithelial Cells Are Less Tolerant to Infection by Staphylococcus aureus

Hsieh

Lin

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway and provides reducing energy to all cells by maintaining redox balance. The most common clinical manifestations in patients with G6PD deficiency are neonatal jaundice and acute hemolytic anemia. The effects of microbial infection in patients with G6PD deficiency primarily relate to the hemolytic anemia caused by Plasmodium or viral infections and the subsequent medication that is required. We are interested in studying the impact of bacterial infection in G6PD-deficient cells. G6PD knock down A549 lung carcinoma cells, together with the common pathogen Staphylococcus aureus, were employed in our cell infection model. Here, we demonstrate that a lower cell viability was observed among G6PD-deficient cells when compared to scramble controls upon bacterial infection using the MTT assay. A significant increase in the intracellular ROS was detected among S. aureus-infected G6PD-deficient cells by observing dichlorofluorescein (DCF) intensity within cells under a fluorescence microscope and quantifying this signal using flow cytometry. The impairment of ROS removal is predicted to enhance apoptotic activity in G6PD-deficient cells, and this enhanced apoptosis was observed by annexin V/PI staining under a confocal fluorescence microscope and quantified by flow cytometry. A higher expression level of the intrinsic apoptotic initiator caspase-9, as well as the downstream effector caspase-3, was detected by Western blotting analysis of G6PD-deficient cells following bacterial infection. In conclusion, we propose that bacterial infection, perhaps the secreted S. aureus α-hemolysin in this case, promotes the accumulation of intracellular ROS in G6PD-deficient cells. This would trigger a stronger apoptotic activity through the intrinsic pathway thereby reducing cell viability when compared to wild type cells.

show abstract

Severe glucose-6-phosphate dehydrogenase deficiency leads to susceptibility to infection and absent NETosis

Siler

Romão

Tejera

et al. 2017

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Because severe G6PD deficiency can be a phenocopy of chronic granulomatous disease with regard to the cellular and clinical phenotype, careful evaluation of neutrophil function seems mandatory in these patients to decide on appropriate anti-infective preventive measures. Determining the level of G6PD enzyme activity should be followed by analysis of reactive oxygen species production and NET formation to decide on required antibiotic and antimycotic prophylaxis.

show abstract

Treatment of MRSA Infections in an African-American Male with G6PD Deficiency

Cited by 4 publications

References 24 publications

Glucose-6-Phosphate Acts as an Extracellular Signal of SagS To Modulate Pseudomonas aeruginosa c-di-GMP Levels, Attachment, and Biofilm Formation

Glucose-6-Phosphate Acts as an Extracellular Signal of SagS To Modulate Pseudomonas aeruginosa c-di-GMP Levels, Attachment, and Biofilm Formation

Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Epithelial Cells Are Less Tolerant to Infection by Staphylococcus aureus

Severe glucose-6-phosphate dehydrogenase deficiency leads to susceptibility to infection and absent NETosis

Contact Info

Product

Resources

About