Systems Epigenomics of Persistent Bloodstream Infection

持续性血流感染的系统表观基因组学

• 批准号: 10551703
• 负责人: Michael R Yeaman
• 金额: $ 230.46万
• 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/10551703
• 关键词: Acceleration; Address; Algorithms; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antifungal Agents; Antigens; Automobile Driving; Bacteremia; Bioinformatics; Blood; Blood Circulation; Candida; Candida albicans; Centers for Disease Control and Prevention (U.S.); Chromosomal Rearrangement; Clinical; Communicable Diseases; Computer Models; Computing Methodologies; DNA Methylation; Data; Data Set; Detection; Diagnostic; Disease; Disseminated candidiasis; Emergency Situation; Epigenetic Process; Etiology; Experimental Models; Fungemia; Gene Expression; Gene Rearrangement; Genetic; Genotype; Goals; Healthcare; Hematogenous; Hospital Mortality; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunologic Memory; Immunotherapeutic agent; In Vitro; Infection; Intensive Care Units; Intervention; Laboratories; Laboratory Study; Length of Stay; Libraries; Life; Macrophage; Mediating; Memory; Methods; Microbial Biofilms; Modeling; Molecular; Morbidity - disease rate; Nosocomial Infections; Organ; Outcome; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Phenotype; Predisposition; Process; Productivity; Receptor Signaling; Refractory; Research; Research Project Grants; Resistance; Risk; STAT protein; STAT1 protein; Sepsis; Specificity; Staphylococcus aureus; Stress; Study models; System; Systems Biology; Technology; Testing; Therapeutic; Tissues; Training; Translating; United States National Institutes of Health; Variant; Virulence; Work; antimicrobial; antimicrobial drug; antimicrobial tolerance; biobank; candidemia; cell injury; chronic infection; complex data; cytokine; data management; effective therapy; epigenetic memory; epigenome; epigenomics; high risk; improved; in vivo; innate immune mechanisms; innovation; insight; methicillin resistant Staphylococcus aureus; methylomics; mortality; mouse model; neutrophil; novel; novel strategies; pathogen; pharmacologic; prediction algorithm; predictive modeling; prevent; programs; prospective; prototype; response; screening; sex; success; synergism; therapeutic candidate; vaccine strategy

PROJECT ABSTRACT Persistent bloodstream infections are life-threatening infectious disease emergencies posing significant challenges to effective treatment. Such infections occur when a pathogen is susceptible to an anti-infective agent in vitro but is not cleared from the bloodstream in vivo when that anti-infective agent is used appropriately. As a result, anti-infective usage increases, accelerating alarming increases in anti-infective resistance. This vicious cycle of persistence driving anti- infective escalation driving resistance is an NIH high–priority concern. Bloodstream infections caused by Staphylococcus aureus (SA) or Candida albicans (CA) are increasingly common. Of urgent concern, up to 35% of patients with methicillin-resistant SA (MRSA) persistent bacteremia succumb even on gold-standard therapy. Likewise, in patients with hematogenously disseminated candidiasis (HDC), mortality is 39% overall and 47% in those in the intensive care unit, despite appropriate treatment. A disease mystery is central to such infections: the causative pathogen is susceptible to antimicrobials in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from classical antibiotic resistance. Rather, persistent MRSA or CA are elusive: they adapt to host immune responses and antibiotic stresses uniquely in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for persistent MRSA or CA bloodstream infections. Hence, there is a critical, unmet need to understand the unique interactions of the human, pathogen and therapeutic factors driving persistence outcomes. Based on our extensive preliminary data, we believe that persistent infections caused by MRSA and CA result from a three-way interaction of the pathogen, host immune response and antimicrobial agent in vivo. We hypothesize that persistent isolates: 1) have specific epigenomes to enable persistence; 2) subvert innate immune programming and memory for immune evasion; 3) evoke non-protective or maladaptive immune responses; and 4) exploit contextual immunity as persistence reservoirs. We further posit that conventional approaches to study this clinically urgent phenomenon are insufficient to understand it. We have developed three independent but synergistic research Projects to overcome these limitations. Each Project brings proven strengths and innovative approaches to bear on Specific Aims that synergize via a systems-based approach supported by outstanding technology, bioinformatics and computational Cores. Here, we will use state-of-the-art technologies to comprehensively analyze the genetics and epigenetics of pathogens and the host immune system in context of antimicrobial therapy in laboratory studies and experimental models of infection. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. By understanding these factors and their interactions, new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. These goals are ideally aligned with priorities of the National Institutes of Health and Centers for Disease Control & Prevention.

项目摘要 持续的血液感染是威胁生命的感染性疾病，紧急构成了重大挑战 进行有效的治疗。当病原体在体外受到抗感染剂的影响时，就会发生这种感染 当适当使用该抗感染剂时，从血液中的体内清除。结果，反感染用法 增加，加速抗感染抗性的令人震惊的增加。这种持久性的恶性循环驱动抗 感染性升级驱动阻力是NIH的高度问题。由 金黄色葡萄球菌（SA）或白色念珠菌（CA）越来越普遍。紧急关注的是，多达35％ 耐甲氧西林SA（MRSA）的患者即使在金色标准疗法上也屈服于持续的细菌。同样地， 在血源性传播念珠菌病（HDC）的患者中，死亡率总计39％，其中患者为47％。 重症监护病房，目的地适当的治疗。一种神秘的疾病是这种感染的核心：病因 在实验室测试中，病原体容易受到抗菌剂的影响，但不在人类中。重要的是，持久性 反映了与经典抗生素耐药性不同的独特类型的治疗效率感染。相反，持久 MRSA或CA难以捉摸：它们适应宿主免疫回报和抗生素应力在体内独特，然后还原 快速在体外。目前，持续的MRSA或CA血液感染的治疗选择很少。因此， 了解人类，病原体和治疗因素的独特相互作用有至关重要的需求 驾驶持久性结果。 根据我们广泛的初步数据，我们认为由MRSA和CA引起的持续感染是由 病原体，宿主免疫反应和体内抗菌剂的三向相互作用。我们假设这一点 持续的孤立株：1）具有特定的表格来实现持久性； 2）颠覆先天的免疫程序 和免疫驱虫的记忆； 3）唤起非保护或不良适应性免疫回报； 4）利用 上下文免疫作为持久性水库。我们进一步确认，传统的方法在临床上研究这一问题 紧急现象不足以理解它。我们已经开发了三项独立但协同的研究 克服这些限制的项目。每个项目都会带来验证的优势和创新的方法 通过杰出技术，生物信息学和 计算核心。在这里，我们将使用最先进的技术来全面分析遗传学和 在实验室研究中，病原体和宿主免疫系统的表观遗传学 感染的实验模型。反过来，将使用强大的生物信息学和计算来分析这些数据 检测大型复杂数据集中隐藏模式的方法。通过了解这些因素及其相互作用， 可以开发和应用新的识别和治疗高风险患者的方法来改善和挽救生命。这些 理想的目标与美国国立卫生研究院和疾病控制与预防中心的优先事项保持一致。