Systems Immunolobiology of Antibiotic-Persistent MRSA Infection

抗生素持续性 MRSA 感染的系统免疫学

• 批准号: 9108773
• 负责人: Michael R Yeaman
• 金额: $ 199.99万
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-03-21 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108773
• 关键词: Advisory Committees; Algorithms; Americas; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Automobile Driving; Bacteremia; Bacteria; Bacterial Drug Resistance; Biological Process; Blood Circulation; Cells; Centers for Disease Control and Prevention (U.S.); Cereals; Chromosomes; Clinical; Communicable Diseases; Complex; Daptomycin; Data; Data Set; Development; Experimental Models; Exposure to; Foundations; Genes; Genetic; Genetic Determinism; Genomics; Glycopeptide Antibiotics; Goals; Gold; Growth; Human; Immune; Immune response; Immune system; Immunobiology; Immunogenetics; Immunology; Immunophenotyping; In Vitro; Infection; Integration Host Factors; Intervention; Knowledge; Laboratories; Lead; Leadership; Life; Methicillin Resistance; Methods; Microbial Biofilms; Modeling; Mus; Oryctolagus cuniculus; Outcome; Patients; Pattern; Phenotype; Predisposition; Process; Relapse; Research; Risk; Sampling; Sepsis; Societies; Staphylococcus aureus; System; Systems Biology; Techniques; Testing; Therapeutic; United States National Institutes of Health; Ursidae Family; Validation; Vancomycin; analytical tool; base; biobank; clinically relevant; comparative; experience; genetic analysis; high risk; improved; in vivo; innovation; insight; member; methicillin resistant Staphylococcus aureus; microbial; mutant; novel; novel strategies; pathogen; prediction algorithm; prevent; public health relevance; research clinical testing; resistant strain; response; transcriptomics

 DESCRIPTION (provided by applicant): Staphylococcus aureus bacteremia (SAB) is a common and life-threatening bloodstream infection that is often caused by methicillin-resistant strains (MRSA). Of urgent concern, up to 30% of SAB patients fail antibiotic treatment even when gold-standard anti-MRSA therapy (vancomycin [VAN] or daptomycin (DAP]) is used. These patients have persistent bacteremia, which frequently results in a dismal clinical outcome. Even though the MRSA isolates from these patients appear to be "susceptible" to VAN or DAP based upon in vitro CLSI breakpoints, these antibiotics fail to clear the bloodstream infection. Such in vivo antibiotic resistance is termed Antibiotic-Persistent MRSA Bacteremia, or APMB. At present, there are few therapeutic options for these life-threatening infections. There is a critical, unmet need to understand the unique intersection of host and pathogen factors driving APMB. Elucidating these factors holds promise to lead to new approaches to prospectively identify patients at risk for developing APMB, and novel strategies to prevent or treat this often devastating infection. Importantly, APMB represents a unique subset of antibiotic resistant infections that differ from biofilm-associated infections due to "antibiotic-tolerant" or "recalcitrant / relapsing" isolates. APMB isolates are genetically stable, but highly adaptive strains induced by in vivo antibiotic exposure. Thus, mechanisms of persistent infections (APMB) are distinct from antibiotic-tolerant infections. Based on our extensive preliminary data, we hypothesize that APMB results from a three-way interaction among the pathogen, host immune response and antibiotic. We further posit that conventional approaches to study this clinically important phenomenon may be insufficient to understand it. Therefore, we will: 1) analyze the interactions of wild-type and mutant APMB strains with host cells and constituents in vitro, ex vivo, and in discriminative animal models to resolve key genotypic & phenotypic determinants of the S. aureus persistome that drives APMB; 2) leverage our pioneering S. aureus Bacteremia Group (SABG) biorepository of human samples & matched clinical isolates, genomic & transcriptional analysis, and immunophenotyping to define host genetic and immune profiles of APMB during VAN or DAP treatment; and 3) use our powerful systems-based statistical and computational immunology approaches to integrate results of high-throughput genomics and transcriptomics data across studies to model the pathogen-host signatures unique to APMB. Therefore, we will resolve the pathogen and host factors that drive APMB to enable innovative approaches to predict, prevent and treat MRSA bloodstream infections that persist despite antibiotic treatment. These critically needed advances will derive from iterative refinement of studies that bring together proven strengths of an outstanding research team to apply an integrated, systems-based approach. The result will yield robust predictive algorithms for clinical evaluation for improved interventions against MRSA infections. Thus, through leading-edge methods and strategies that are optimized for synergy, our progressively focused studies in this U01 project are ideally responsive to the priorities of the NIH and this "Systems Biology of Antibacterial Resistance" RFA (RFA-AI-14-064).

 描述（由适用提供）：金黄色葡萄球菌细菌（SAB）是一种常见且威胁生命的血液感染，通常是由耐甲氧西林菌株（MRSA）引起的。紧急关注的是，即使使用黄金标准抗MRSA治疗（Van霉素[VAN]或DAPTOMYCIN（DAP）），最多30％的SAB患者也无法抗生素治疗。这些患者持续存在细菌。这些患者经常导致临床结果降低。无法清除血液的感染。 APMB以及预防或治疗这种灾难性感染的新型策略。 “顽固 /复发”分离株。 APMB分离株在遗传上是稳定的，但是由体内抗生素暴露引起的高度适应性菌株。持续感染（APMB）的机制与耐生性感染不同。根据我们广泛的初步数据，我们假设APMB是由于病原体，宿主免疫反应和抗生素之间的三向相互作用而引起的。我们进一步确认，研究这种临床上重要现象的常规方法可能不足以理解它。因此，我们将：1）分析野生型和突变体APMB菌株与宿主细胞和体外的宿主细胞和成分的相互作用，在体外以及歧视性动物模型中，以解决驱动APMB的关键基因型和现象的决定剂，以驱动APMB； 2）利用人类样品和匹配的临床分离株，基因组和转录分析以及免疫表型的生物验证链球菌菌群（SABG）生物位，以定义货车或DAP治疗期间APMB的宿主遗传和免疫学谱； 3）使用我们强大的基于系统的统计和计算免疫学方法来跨研究的高通量基因组学和转录组数据的综合结果，对APMB独有的病原体宿主签名进行建模。因此，我们将解决驱动APMB的病原体和宿主因素，以实现创新方法，以预测，预防和治疗尽管治疗抗生素治疗的MRSA血液感染。这些至关重要的进步将从迭代的研究中得出，这些研究将杰出的研究团队的经过验证的优势融合在一起，以采用一种基于系统的综合方法。结果将产生可靠的预测算法，以改善针对MRSA感染的干预措施。因此，通过针对协同作用优化的领先方法和策略，我们在U01项目中逐步专注的研究理想地响应了NIH的优先级和这种“抗菌抗性系统生物学” RFA（RFA-AI-AI-14-14-064）。