Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.

Abstract

The role of the host in development of persistent methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent methicillin-resistant <i>S. aureus</i> bacteremia (PB) and resolving methicillin-resistant <i>S. aureus</i> bacteremia (RB) 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 <i>DNMT3A</i> intronic region of chromosome 2p with no impact in messenger RNA (mRNA) expression was more common in RB (21 of 34, 61.8%) than PB (3 of 34, 8.8%) patients (<i>P</i> = 7.8 × 10^-6). Patients with MRSA bacteremia and g.25498283A > C genotype exhibited significantly higher levels of methylation in gene-regulatory CpG island regions (Δmethylation = 4.1%, <i>P</i> < 0.0001) and significantly lower serum levels of interleukin-10 (IL-10) than patients with MRSA bacteremia without <i>DNMT3A</i> mutation (A/C: 9.7038 pg/mL vs. A/A: 52.9898 pg/mL; <i>P</i> = 0.0042). Expression of <i>DNMT3A</i> was significantly suppressed in patients with <i>S. aureus</i> bacteremia and in <i>S. aureus</i>-challenged primary human macrophages. Small interfering RNA (siRNA) silencing of <i>DNMT3A</i> expression in human macrophages caused increased IL-10 response upon <i>S. aureus</i> stimulation. Treating macrophages with methylation inhibitor 5-Aza-2'-deoxycytidine resulted in increased levels of IL-10 when challenged with <i>S. aureus</i> In the murine sepsis model, methylation inhibition increased susceptibility to <i>S. aureus</i> These findings indicate that g.25498283A > C genotype within <i>DNMT3A</i> contributes to increased capacity to resolve MRSA bacteremia, potentially through a mechanism involving increased methylation of gene-regulatory regions and reduced levels of antiinflammatory cytokine IL-10.