Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (10), p.1-11
• Main Authors: Chang, Yu-Ling, Rossetti, Maura, Gjertson, David W., Rubbi, Liudmilla, Thompson, Michael, Montoya, Dennis J., Morselli, Marco, Ruffin, Felicia, Hoffmann, Alexander, Pellegrini, Matteo, Fowler, Vance G., Yeaman, Michael R., Reed, Elaine F.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - administration & dosage; Antibiotics; Antiinfectives and antibacterials; Bacteremia; Bacteremia - drug therapy; Bacteremia - metabolism; Binding sites; Biological Sciences; Bisulfite; CCAAT-Enhancer-Binding Protein-beta - metabolism; CCAAT/enhancer-binding protein; Deoxyribonucleic acid; DNA; DNA Methylation; Drug resistance; Female; Glucocorticoids; Histone acetyltransferase; Humans; Immune system; Leukocytes (neutrophilic); Male; Methicillin; Methicillin-Resistant Staphylococcus aureus - metabolism; Middle Aged; p300-CBP Transcription Factors - metabolism; Response Elements; Signatures; Staphylococcal Infections - drug therapy; Staphylococcal Infections - metabolism; Staphylococcus aureus; Staphylococcus infections; Stat1 protein; STAT1 Transcription Factor - metabolism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2000663118

Persistent 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-β (C/EBPβ) 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.