Genetic Variation of DNA Methyltransferase-3A Contributes to Protection Against Persistent MRSA Bacteremia in Patients.

The role of the host in the development of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent (PB) and resolving (RB) MRSA bacteremia matched by sex, age, race, hemodialysis status, diabetes mellitus, and presence of implantable medical device was studied to gain insights into this question. One heterozygous g.25498283A>C polymorphism located in the DNMT3A intronic region of chromosome 2p was significantly more common in RB (21/34, 61.8%) than PB (3/34, 8.8%) patients (p = 7.8 x10-6). Patients with MRSA bacteremia and the g.25498283A>C genotype exhibited significantly higher levels of methylation in gene regulatory CpG island regions (? methylation = 4.1%, p < 0.0001) and significantly lower serum levels of IL-10 than patients with MRSA bacteremia without the DNMT3A mutation (A/C: 9.7038 pg/ml vs A/A: 52.9898 pg/ml; p = 0.0042). Expression of DNMT3A was significantly suppressed in patients with S. aureus bacteremia and in S. aureus–challenged primary human macrophages. siRNA silencing of DNMT3A expression in human macrophages caused increased IL-10 response upon S. aureus stimulation. Treating macrophages with the methylation inhibitor 5-Aza-2'-deoxycytidine also resulted in increased levels of IL-10 when challenged with S. aureus. In the murine sepsis model, methylation inhibition increased susceptibility to S. aureus. These findings indicate that the g.25498283A>C genotype within DNMT3A contributes to an increased capacity to resolve MRSA bacteremia, potentially through a mechanism involving increased methylation of gene regulatory regions, and reduced levels of the anti-inflammatory cytokine IL-10.