Epigenomic Mechanisms & Contextual Immunity in Persistent MRSA Bacteremia

表观基因组机制

• 批准号: 10551708
• 负责人: Michael R Yeaman
• 金额: $ 52.83万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551708
• 关键词: Acceleration; Address; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Automobile Driving; Bacteremia; Bioinformatics; Biological Assay; Blood; Blood Circulation; Cessation of life; Characteristics; Clinical; Clinical Trials; Computing Methodologies; Cross-Priming; DNA; DNA Methylation; DNA Modification Methylases; Data; Data Set; Diagnostic; Dimensions; Emergency Situation; Epigenetic Process; Equation; Etiology; Experimental Models; Foundations; Gene Deletion; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Health Priorities; Hematogenous; Human; Immune; Immune response; Immunity; Immunologic Memory; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Interleukin-10; Intervention; Kidney; Knowledge; Laboratories; Life; Macrophage; Maps; Mediating; Memory; Methods; Methylation; Methyltransferase; Microbial Biofilms; Molecular; Mus; Organism; Outcome; Patients; Pattern; Phagosomes; Phenotype; Predisposition; Production; Rag1 Mouse; Refractory; Regimen; Research; Sepsis; Shapes; Specific qualifier value; Spleen; Staphylococcus aureus; Staphylococcus aureus infection; Stress; System; Systems Biology; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Training; Translating; United States National Institutes of Health; Vaccination; Vaccines; Vancomycin; Variant; Virulence; adaptive immunity; antibiotic tolerance; chronic infection; cohort; comparative; complex data; cytokine; design; epigenomics; experience; genome sequencing; high risk; human DNA; improved; in vivo; inhibitor; innovation; insight; male; methicillin resistant Staphylococcus aureus; multi-drug resistant pathogen; neutrophil; novel; novel strategies; pathogen; pharmacologic; prevent; priority pathogen; protective efficacy; resistance gene; sex; single molecule real time sequencing; success; synergism; translatable strategy; vaccine strategy; virulence gene; whole genome

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.

项目总结/摘要 金黄色葡萄球菌（SA）是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，高达35%的患者即使在金标准抗生素治疗下也会死亡， 仅在美国每年就有近20，000人死亡。在许多MRSA菌血症病例中， 体外抗生素，但即使在适当的治疗下也不能从血液中清除。MRSA在体内的存活， 体外抗生素敏感性称为抗生素持久性。持续性MRSA菌血症（PB）是一种危及生命的 与恶化的结果和抗生素使用升级相关的紧急情况。这种持续的恶性循环 推动抗生素升级，推动抗生素耐药性是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分离株在实验室中对抗生素敏感 但不是在人类身上。重要的是，持续性反映了一种独特的治疗难治性感染 与生物膜介导的或经典的抗生素耐受性或耐药性不同。相反，持续的MRSA是难以捉摸的：他们 在体内适应宿主免疫反应和抗生素应激，然后在体外迅速恢复。目前， 因MRSA引起的PB的治疗选择。此外，尽管进行了几次有价值的尝试，但靶向MRSA的疫苗仍存在一些问题。 到目前为止，在临床试验中尚未达到有效性。因此，有一个关键的，未满足的需要，以定义人类的相互作用， MRSA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，这些目标与 其他项目和核心：1）指定MRSA适应性持续存在的遗传和表观遗传机制， 体内; 2）辨别持续性MRSA如何破坏免疫记忆;以及3）定义保护性与非保护性免疫 区分MRSA持续性与解决结果的背景。我们将采用最先进的技术， 全面分析在抗生素、宿主性别、 以及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进行分析， 计算方法来检测大型复杂数据集中的隐藏模式。除了新的机械见解，我们的 创新研究旨在发现克服MRSA持久性的可翻译干预措施。这些知识 将加速预测、预防和治疗PB感染的新策略，以改善和挽救生命。战略成功 在解决MRSA持续性方面，也可应用于由其他高优先级MDR病原体引起的感染。我们 实现这些目标的基于系统的方法与美国国立卫生研究院的优先事项理想地一致。