Differential signaling effects of Escherichia coli and Staphylococcus aureus in human whole blood indicate distinct regulation of the NRF2 Pathway
Escherichia coli and Staphylococcus aureus are two of the most common bacterial species responsible for severe 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 utilized 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 (up and down-regulated) of  >5000 genes for each experimental condition, with a slight increase in gene dysregulation by S. aureus. While there was significant overlap regarding pro-inflammatory gene ontology pathways, heat-killed E. coli had a more considerable impact on purine metabolism than heat-killed S. aureus, which had a more significant effect on nitric oxide-mediated processes. Utilizing Ingenuity Pathway Analysis, it was predicted that nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, a main transcription factor in anti-oxidant responses, was predominately up-regulated in S. aureus relative to E. coli. Further, the use of pharmacologics that preferentially targeted the Nrf2 pathway led to differential cytokine profiles depending on the type of bacterial exposure. These findings reveal a significant inflammatory dysregulation between E. coli and S. aureus and provide insight into the potential of targeting unique pathways to curb the bacteria species-specific response. Overall design: Total of 12 samples were analyzed, 4 were human whole blood exposure to heat-killed E. coli (HKEC),  4 were human whole blood exposure to heat-killed S. aureus (HKSA). RNA was extracted from each of these samples for bulk RNA-Sequencing analysis.