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

Publication ,  Journal Article
Mba Medie, F; Sharma-Kuinkel, BK; Ruffin, F; Chan, LC; Rossetti, M; Chang, Y-L; Park, LP; Bayer, AS; Filler, SG; Ahn, R; Reed, EF; Gjertson, D ...
Published in: Proc Natl Acad Sci U S A
October 1, 2019

The role of the host in development of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is not well understood. A cohort of prospectively enrolled patients with persistent methicillin-resistant S. aureus bacteremia (PB) and resolving methicillin-resistant S. aureus 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 DNMT3A 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 (P = 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%, P < 0.0001) and significantly lower serum levels of interleukin-10 (IL-10) than patients with MRSA bacteremia without 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. Small interfering RNA (siRNA) silencing of DNMT3A expression in human macrophages caused increased IL-10 response upon S. aureus stimulation. Treating macrophages with methylation inhibitor 5-Aza-2'-deoxycytidine 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 g.25498283A > C genotype within DNMT3A 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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 1, 2019

Volume

116

Issue

40

Start / End Page

20087 / 20096

Location

United States

Related Subject Headings

  • Staphylococcal Infections
  • Polymorphism, Genetic
  • Middle Aged
  • Methicillin-Resistant Staphylococcus aureus
  • Male
  • Macrophages
  • Interleukin-10
  • Humans
  • Host-Pathogen Interactions
  • Genotype
 

Citation

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Mba Medie, F., Sharma-Kuinkel, B. K., Ruffin, F., Chan, L. C., Rossetti, M., Chang, Y.-L., … MRSA Systems Immunobiology Group, . (2019). Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients. Proc Natl Acad Sci U S A, 116(40), 20087–20096. https://doi.org/10.1073/pnas.1909849116
Mba Medie, Felix, Batu K. Sharma-Kuinkel, Felicia Ruffin, Liana C. Chan, Maura Rossetti, Yu-Ling Chang, Lawrence P. Park, et al. “Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.Proc Natl Acad Sci U S A 116, no. 40 (October 1, 2019): 20087–96. https://doi.org/10.1073/pnas.1909849116.
Mba Medie F, Sharma-Kuinkel BK, Ruffin F, Chan LC, Rossetti M, Chang Y-L, et al. Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients. Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):20087–96.
Mba Medie, Felix, et al. “Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients.Proc Natl Acad Sci U S A, vol. 116, no. 40, Oct. 2019, pp. 20087–96. Pubmed, doi:10.1073/pnas.1909849116.
Mba Medie F, Sharma-Kuinkel BK, Ruffin F, Chan LC, Rossetti M, Chang Y-L, Park LP, Bayer AS, Filler SG, Ahn R, Reed EF, Gjertson D, Yeaman MR, Fowler VG, MRSA Systems Immunobiology Group. Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients. Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):20087–20096.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

October 1, 2019

Volume

116

Issue

40

Start / End Page

20087 / 20096

Location

United States

Related Subject Headings

  • Staphylococcal Infections
  • Polymorphism, Genetic
  • Middle Aged
  • Methicillin-Resistant Staphylococcus aureus
  • Male
  • Macrophages
  • Interleukin-10
  • Humans
  • Host-Pathogen Interactions
  • Genotype