164 Chapter 8 mutation revealed significantly higher levels of methylation in gene-regulatory CpG island regions in patients expressing the homozygous genotype. Cytokine analysis also revealed significantly lower levels of anti-inflammatory cytokine interleukin-10 (IL-10) in acute phase serum from patients with resolving MRSAB compared to persistent MRSAB (114 pg/mL in persistent bacteremia patients vs. 13.1 pg/mL in resolving bacteremia patients; p = 0.009). IL-10 levels were also found to be lower in the subset of patients with the g.25498283A > C polymorphism, regardless of whether the serum was from patients with persistent MRSAB or resolving MRSAB (A/C: 18.9 pg/mL vs. A/A: 68.9 pg/mL in patients with persistent MRSAB and A/C:8.7 pg/mL vs. A/A:14.95 pg/mL in patients with resolving MRSAB). The proposed mechanism for decreased susceptibility to persistent MRSAB is thought to revolve around suppression of IL-10 production via DNA-methyltransferase-3A-mediated DNA methylation (Figure 1). While the exact role of IL-10 in promoting persistent MRSAB is unclear, this finding was consistent with prior studies that also found an association between elevated IL-10 and mortality from SAB and persistent SAB [13,47]. IL-10 is an immunosuppressive cytokine and is known to prevent the activation of Th1 helper T cells and subsequently can increase survival of some intracellular bacteria [48]. It is known that IL-10 signaling can suppress proinflammatory macrophage and cytokine production, resulting in less reactive oxygen species (ROS) and reactive nitrogen species (RNS) known to play a crucial role in fighting S. aureus and other pathogens [48–52]. One can hypothesize that the reduced IL-10 production in patients with the g.25498283A > C polymorphism allows for a more robust pro-inflammatory response, which assists with efficient clearance of bacteria from the bloodstream. However, more research in this field is needed to further unravel the complex mechanism. A 2020 follow-up study by Chang et al. examined the DNA methylation pattern in leukocytes from 142 patients with persistent MRSAB (blood culture positive >5 days; n = 70) and resolving MRSAB (blood culture positive <5 days; n = 72) [53]. This study used advanced sequencing techniques to quantify and localize differences in the DNA methylome. DNA extracted from persistent MRSAB patients’ leukocytes exhibited significantly lower levels of methylation localized to binding sites for two transcription factors involved in immune regulation: signal transducer/activator of transcription 1 (STAT1) and CCAAT enhancer binding protein-β (C/EBPβ) (Figure 2). In contrast, the profile of the resolving MRSAB patients’ methylome localized differences in the histone acetyltransferase p300 and glucocorticoid receptor binding site. The mechanistic basis for these changes is proposed by the authors. Firstly, C/ EBPβ has a role in emergency granulopoiesis [54], and the abundance of immature granulocytes arising from activation of the C/EBPβ gene may impair the ability of the immune system to assimilate the circulating bacteria, promoting persistence.
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