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).