AuthorAcceptedPNASManuscript.pdf (24.79 MB)
Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia
journal contribution
posted on 2023-06-10, 03:42 authored by Yu-Ling Chang, Maura Rossetti, David W Gjertson, Liudmilla Rubbi, Michael Thompson, Dennis J Montoya, Marco Morselli, Felicia Ruffin, Alexander Hoffmann, Matteo Pellegrini, Vance G Fowler, Michael R Yeaman, Elaine F Reed, Simon MitchellSimon Mitchell, the MRSA Systems Immunology Group, othersPersistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is life threatening and occurs in up to 30% of MRSA bacteremia cases despite appropriate antimicrobial therapy. Isolates of MRSA that cause antibiotic-persistent methicillin-resistant S. aureus bacteremia (APMB) typically have in vitro antibiotic susceptibilities equivalent to those causing antibiotic-resolving methicillin-resistant S. aureus bacteremia (ARMB). Thus, persistence reflects host–pathogen interactions occurring uniquely in context of antibiotic therapy in vivo. However, host factors and mechanisms involved in APMB remain unclear. We compared DNA methylomes in circulating immune cells from patients experiencing APMB vs. ARMB. Overall, methylation signatures diverged in the distinct patient cohorts. Differentially methylated sites intensified proximate to transcription factor binding sites, primarily in enhancer regions. In APMB patients, significant hypomethylation was observed in binding sites for CCAAT enhancer binding protein-ß (C/EBPß) and signal transducer/activator of transcription 1 (STAT1). In contrast, hypomethylation in ARMB patients localized to glucocorticoid receptor and histone acetyltransferase p300 binding sites. These distinct methylation signatures were enriched in neutrophils and achieved a mean area under the curve of 0.85 when used to predict APMB using a classification model. These findings validated by targeted bisulfite sequencing (TBS-seq) differentiate epigenotypes in patients experiencing APMB vs. ARMB and suggest a risk stratification strategy for antibiotic persistence in patients treated for MRSA bacteremia.
History
Publication status
- Published
File Version
- Accepted version
Journal
Proceedings of the National Academy of Sciences (PNAS)ISSN
0027-8424Publisher
National Academy of SciencesExternal DOI
Issue
10Volume
118Page range
1-11Article number
a2000663118Event location
United StatesDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-05-27First Open Access (FOA) Date
2022-07-26First Compliant Deposit (FCD) Date
2022-07-26Usage metrics
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No categories selectedKeywords
DNA methylationMRSAStaphylococcus aureusepigeneticspersistenceAnti-Bacterial AgentsBacteremiaCCAAT-Enhancer-Binding Protein-betaDNA MethylationFemaleHumansMaleMethicillin-Resistant Staphylococcus aureusMiddle AgedResponse ElementsSTAT1 Transcription FactorStaphylococcal Infectionsp300-CBP Transcription Factors
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