Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia
Human DNA methylation signatures differentiate persistent from resolving MRSA bacteremia
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DOI：
10.1073/pnas.2000663118
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发表时间：
2021-03-09
影响因子：
11.1
通讯作者：
Reed, Elaine F.
中科院分区：
文献类型：
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作者：
Chang, Yu-Ling;Rossetti, Maura;Reed, Elaine F.
持续的耐甲氧西林金黄色葡萄球菌 (MRSA) 菌血症会危及生命，尽管采取了适当的抗菌治疗，仍有高达 30% 的 MRSA 菌血症病例发生。引起抗生素持久性耐甲氧西林金黄色葡萄球菌菌血症 (APMB) 的 MRSA 分离株通常具有与引起抗生素缓解耐甲氧西林金黄色葡萄球菌菌血症 (ARMB) 的菌株相当的体外抗生素敏感性。因此，持久性反映了在体内抗生素治疗背景下独特发生的宿主-病原体相互作用。然而，APMB 涉及的宿主因素和机制仍不清楚。我们比较了经历 APMB 和 ARMB 的患者循环免疫细胞中的 DNA 甲基化组。总体而言，不同患者群体的甲基化特征存在差异。差异甲基化位点在转录因子结合位点附近增强，主要是在增强子区域。在 APMB 患者中，CCAAT 增强子结合蛋白-β (C/EBP beta) 和转录信号转导子/激活子 1 (STAT1) 的结合位点观察到显着的低甲基化。相比之下，ARMB 患者的低甲基化局限于糖皮质激素受体和组蛋白乙酰转移酶 p300 结合位点。这些独特的甲基化特征在中性粒细胞中富集，当使用分类模型预测 APMB 时，曲线下的平均面积达到 0.85。这些结果经过靶向亚硫酸氢盐测序 (TBS-seq) 验证，区分了经历 APMB 和 ARMB 的患者的表观基因型，并提出了针对 MRSA 菌血症治疗患者的抗生素持续使用的风险分层策略。
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-beta (C/EBP beta) 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.