Epigenomic Mechanisms & Contextual Immunity in Persistent MRSA Bacteremia

项目摘要/摘要 金黄色葡萄球菌(SA)是引起菌血症和血源性后遗症最常见的病原体。 在耐甲氧西林金黄色葡萄球菌(MRSA)菌血症中，即使使用黄金标准的抗生素治疗，也有高达35%的患者死亡。 相当于仅在美国每年就有近2万人死亡。在许多耐甲氧西林金黄色葡萄球菌菌血症病例中，分离株是敏感的。 在体外对抗生素产生耐药性，但即使在适当的治疗下也不能从血液中清除。耐甲氧西林金黄色葡萄球菌在体内存活 体外对抗生素的敏感性称为抗生素持久性。持续性耐甲氧西林金黄色葡萄球菌菌血症(PB)是一种危及生命的疾病 与结果恶化和抗生素使用升级相关的紧急情况。这种坚持的恶性循环 推动抗生素升级导致抗生素耐药性是NIH高度优先关注的问题。 一个长期存在的谜团是pb感染的核心：mrsa分离株在实验室对抗生素敏感。 测试--但不是在人体内。重要的是，持久性反映了一种独特的治疗类型--难治性感染 不同于生物膜介导的或经典的抗生素耐受性或耐药性。相反，持久的MRSA是难以捉摸的：他们 在体内适应宿主免疫反应和抗生素压力，然后在体外迅速恢复。目前，几乎没有 耐甲氧西林金黄色葡萄球菌引起的PB的治疗选择。此外，尽管进行了几次有益的尝试，但针对MRSA的疫苗已经 到目前为止，在临床试验中尚未取得疗效。因此，有一个关键的、未得到满足的需求来定义人类的交互作用， 耐甲氧西林金黄色葡萄球菌病原体和抗生素因素驱动持久性结果。 为了应对这些挑战，我们设计了独立的具体目标，与这些目标高度协同 其他项目和核心：1)指定MRSA自适应持续存在的遗传和表观遗传机制 活体；2)辨别持久的MRSA如何颠覆免疫记忆；3)定义保护性免疫与非保护性免疫 区分MRSA持久性与解决结果的上下文。我们将把最先进的技术应用到 在抗生素、宿主性别的背景下，综合分析导致PB结果的动态宿主-病原体关系 以及在体外和实验模型中的时间。反过来，这些数据将使用强大的生物信息学和 用于检测大型复杂数据集中隐藏模式的计算方法。除了新的机械洞察力，我们的 创新研究旨在发现克服耐甲氧西林金黄色葡萄球菌持久性的可翻译干预。这一知识 将加快预测、预防和治疗PB感染的新战略，以改善和挽救生命。策略成功 在处理耐甲氧西林金黄色葡萄球菌时，持久性也可应用于由其他高度优先的多药耐药病原体引起的感染。我们的 实现这些目标的基于系统的方法与国家卫生研究院的优先事项理想地保持一致。

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus (SA) is the most common etiologic agent of bacteremia and hematogenous sequelae. In methicillin-resistant SA (MRSA) bacteremia, up to 35% of patients succumb even on gold-standard antibiotic therapy, equating to nearly 20,000 deaths/year in the U.S. alone. In many cases of MRSA bacteremia, isolates are susceptible to antibiotics in vitro but not cleared from the bloodstream even on appropriate therapy. Survival of MRSA in vivo despite antibiotic susceptibility in vitro is termed antibiotic persistence. Persistent MRSA bacteremia (PB) is a life-threatening emergency correlating with worsened outcomes and escalation of antibiotic use. This vicious cycle of persistence driving antibiotic escalation driving antibiotic resistance is an NIH high–priority concern. A long-standing mystery is central to PB infections: the MRSA isolate is susceptible to antibiotics in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from biofilm-mediated or classical antibiotic tolerance or resistance. Rather, persistent MRSA are elusive: they adapt to host immune responses and antibiotic stresses in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for PB due to MRSA. Further, despite several meritorious attempts, vaccines targeting MRSA have not achieved efficacy in clinical trials to date. Thus, there is a critical, unmet need to define the interactions of the human, MRSA pathogen and antibiotic factors driving persistence outcomes. To address these challenges, we have designed independent Specific Aims that are highly synergistic with those of other Projects & Cores to: 1) specify the genetic and epigenetic mechanisms by which MRSA adaptively persists in vivo; 2) discern how persistent MRSA subvert immune memory; and 3) define protective vs. non-protective immune contexts that differentiate MRSA persistence vs. resolving outcomes. We will apply state-of-the-art technologies to comprehensively analyze dynamic host-pathogen relationships leading to PB outcomes in context of antibiotic, host sex and time in vitro and in experimental models. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. Beyond new mechanistic insights, our innovative studies are designed to discover translatable interventions that overcome MRSA persistence. This knowledge will accelerate new strategies to predict, prevent and treat PB infections to improve and save lives. Strategies successful in addressing MRSA persistence may also be applied to infections caused by other high-priority MDR pathogens. Our systems-based approach to achieving these goals is ideally aligned with priorities of the National Institutes of Health.