Affiliation:
1. Vanderbilt University Medical Center, Nashville, Tennessee
2. Vanderbilt University, Creative Data Solutions, Nashville, Tennessee
Abstract
ABSTRACT
Escherichia coli and Staphylococcus aureus are two of the most common bacterial species responsible for sepsis. While it is observed that they have disparate clinical phenotypes, the signaling differences elicited by each bacteria that drive this variance remain unclear. Therefore, we used human whole blood exposed to heat-killed E. coli or S. aureus and measured the transcriptomic signatures. Relative to unstimulated control blood, heat-killed bacteria exposure led to significant dysregulation (upregulated and downregulated) of >5,000 genes for each experimental condition, with a slight increase in gene alterations by S. aureus. While there was significant overlap regarding proinflammatory pathways, Gene Ontology overrepresentation analysis of the most altered genes suggested biological processes like macrophage differentiation and ubiquinone biosynthesis were more unique to heat-killed S. aureus, compared with heat-killed E. coli exposure. Using Ingenuity Pathway Analysis, it was demonstrated that nuclear factor erythroid 2-related factor 2 signaling, a main transcription factor in antioxidant responses, was predominately upregulated in S. aureus exposed blood relative to E. coli. Furthermore, the use of pharmacologics that preferentially targeted the nuclear factor erythroid 2-related factor 2 pathway led to differential cytokine profiles depending on the type of bacterial exposure. These findings reveal significant inflammatory dysregulation between E. coli and S. aureus and provide insight into the targeting of unique pathways to curb bacteria-specific responses.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Reference46 articles.
1. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study;Lancet,2020
2. Late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies;Mil Med Res,2019
3. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery;Surgery,2018
4. The end of “one size fits all” sepsis therapies: toward an individualized approach;Biomedicines,2022
5. Protein-mediated interactions in the dynamic regulation of acute inflammation;Biocell,2023