Systems Immunolobiology of Antibiotic-Persistent MRSA Infection

抗生素持续性 MRSA 感染的系统免疫学

基本信息

批准号：
9246423
负责人：
Michael R Yeaman
金额：
$ 194.12万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9246423
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 Biometry Blood Circulation Cells Centers for Disease Control and Prevention (U.S.)Cereals Chromosomes Clinical Communicable Diseases Complex Custom Daptomycin Data Data Set Development Experimental Models Exposure to Foundations Genes Genetic Genetic Determinism Genetic Transcription Genomics Genotype 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 Patient Isolators Patient risk Patients Pattern Phenotype Predisposition Process Relapse Research Risk Sampling Sepsis Societies Staphylococcal Infections 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 high risk improved in vivo innovation insight member microbial mutant novel novel strategies pathogen prediction algorithm prevent prospective public health relevance research clinical testing resistant strain response synergism transcriptomics

项目摘要

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：金黄色葡萄球菌菌血症（SAB）是一种常见的，生命线的感染通常是通过耐甲氧西林的菌株（MRSA）的原因（MRSA）。使用MRSA治疗（VAN]或DACTOMYCIN（DAP））。这些患者患有持续性的双肌血症，经常以令人沮丧的临床结局诱发。即使来自患者的MRSA分离株似乎是基于“易感的”或DAP的。在体外CLSI断裂点，这些抗生素无法清除血液中的病情。驱动APMB的病原体因素有望导致新的方法，以期识别出患有APMB的患者通常会造成灾难性的感染，APMB代表了抗生素耐药性感染的独特子集，这些抗生素抗生素与生物蛋白酶相关的I Nfections差异或者 “顽固的”分离株是遗传稳定的，基于我们广泛的初步数据ze，宿主免疫反应和抗生素可能是临床上重要的现象，这是我们的持续性感染的机制。因此，我们将：1）分析野生型和MUTMB菌株与宿主细胞和征服的体外相互作用，以及在歧视性动物模型中，以解决驱动APMB的金黄色葡萄球菌持久的键盘和型号的决定因素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菌血症组（SABG）生物验证，以定义货车或DAP信任期间APMB的宿主和免疫特征，以整合高通量基因组学和转录基因组学数据研究结果的结果病原体的host属于APMB的病原体和宿主因素，尽管可以预测这些抗生素治疗的方法。方法。将产生预测算法，以改善对MRSA感染的干预措施，因此，通过对协同作用的前沿方法和策略，我们逐渐重点的研究对NIH的优先级和这种“抗活性系统”的重点“ RFA（RFA-AI-14- 064）。