Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia
Yu‐Ling Chang, Maura Rossetti, David W. Gjertson, Liudmilla Rubbi, Michael J. Thompson, Dennis Montoya, Marco Morselli, Felicia Ruffin, Alexander Hoffmann, Matteo Pellegrini, Vance G. Fowler, Michael R. Yeaman, Elaine F. Reed, with the MRSA Systems Immunology Group, Richard Ahn, Arnold S. Bayer, Liana C. Chan, Yu‐Ling Chang, Scott G. Filler, Vance G. Fowler, David Gjertson, Alexander Hoffmann, Felix Mba Medie, Tsuyoshi Mikkaichi, Simon Mitchell, Yan Qin, Elaine F. Reed, Maura Rossetti, Felicia Ruffin, Batu K. Sharma‐Kuinkel, Katherine M. Sheu, Joshua T. Thaden, Alan J. Waring, Yan Q. Xiong, Ying Zheng, Michael R. Yeaman
Abstract
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.