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Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778225/ https://www.ncbi.nlm.nih.gov/pubmed/31527248 http://dx.doi.org/10.1073/pnas.1909849116 |
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author | Mba Medie, Felix Sharma-Kuinkel, Batu K. Ruffin, Felicia Chan, Liana C. Rossetti, Maura Chang, Yu-Ling Park, Lawrence P. Bayer, Arnold S. Filler, Scott G. Ahn, Richard Reed, Elaine F. Gjertson, David Yeaman, Michael R. Fowler, Vance G. |
author_facet | Mba Medie, Felix Sharma-Kuinkel, Batu K. Ruffin, Felicia Chan, Liana C. Rossetti, Maura Chang, Yu-Ling Park, Lawrence P. Bayer, Arnold S. Filler, Scott G. Ahn, Richard Reed, Elaine F. Gjertson, David Yeaman, Michael R. Fowler, Vance G. |
author_sort | Mba Medie, Felix |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6778225 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-67782252019-10-09 Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients Mba Medie, Felix Sharma-Kuinkel, Batu K. Ruffin, Felicia Chan, Liana C. Rossetti, Maura Chang, Yu-Ling Park, Lawrence P. Bayer, Arnold S. Filler, Scott G. Ahn, Richard Reed, Elaine F. Gjertson, David Yeaman, Michael R. Fowler, Vance G. Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2019-10-01 2019-09-16 /pmc/articles/PMC6778225/ /pubmed/31527248 http://dx.doi.org/10.1073/pnas.1909849116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | PNAS Plus Mba Medie, Felix Sharma-Kuinkel, Batu K. Ruffin, Felicia Chan, Liana C. Rossetti, Maura Chang, Yu-Ling Park, Lawrence P. Bayer, Arnold S. Filler, Scott G. Ahn, Richard Reed, Elaine F. Gjertson, David Yeaman, Michael R. Fowler, Vance G. Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients |
title | Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients |
title_full | Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients |
title_fullStr | Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients |
title_full_unstemmed | Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients |
title_short | Genetic variation of DNA methyltransferase-3A contributes to protection against persistent MRSA bacteremia in patients |
title_sort | genetic variation of dna methyltransferase-3a contributes to protection against persistent mrsa bacteremia in patients |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778225/ https://www.ncbi.nlm.nih.gov/pubmed/31527248 http://dx.doi.org/10.1073/pnas.1909849116 |
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