Rapid Emergence of Livestock-associated MRSA ST398: Host-adaptation & Virulence

牲畜相关 MRSA ST398 的快速出现：宿主适应

• 批准号: 8675798
• 负责人: Lance Bradley Price
• 金额: $ 38.99万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-10 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675798
• 关键词: American; Animal Feed; Animal Model; Animals; Antibiotic Resistance; Asia; Back; Bacterial Antibiotic Resistance; Bacteriophages; Biological Assay; Case Study; Clinic; Collection; Communities; Country; Coupled; Denmark; Disease; Elements; Environment; Environmental Health; Epidemiologic Studies; Epidemiology; Europe; European; Evolution; Exhibits; Family suidae; Farming environment; Food; Frequencies; Future; Genes; Genetic Research; Genome; Genomics; Genotype; Geographic Distribution; Household; Human; Immune; In Vitro; Individual; Infant; Infection; Infection Control; Intervention; Investigation; Iowa; Knowledge; Lead; Link; Livestock; Longitudinal Studies; Mediating; Microbial Genetics; Molecular; Netherlands; North America; Northern Europe; Phylogeny; Prevalence; Price; Production; Pseudogenes; Public Health; Qualifying; Relative (related person); Reporting; Research; Research Personnel; Resolution; Role; Route; Rural; Rural Health; Scientist; Sepsis; Simulate; Skin Tissue; Soft Tissue Infections; Structure; Surveillance Program; Surveys; System; Techniques; Technology; Testing; Time; Translational Research; Virulence; Virulence Factors; assay development; base; cost effective; design; experience; farm worker; farmer; fitness; foodborne pathogen; gastrointestinal; genome sequencing; human disease; in vitro Model; innovation; killings; methicillin resistant Staphylococcus aureus; neutrophil; pathogen; public health relevance; repository; surveillance strategy; tool; transmission process

DESCRIPTION (provided by applicant): Since its discovery in 2004, livestock-associated MRSA ST398 has emerged as an increasingly common cause of human infections in Northern Europe and a prevalent colonizer of livestock and farm workers in the U.S. and around the world. A recent survey of Iowa hog farms showed that 70% of farms-and nearly half of the hog farmers-were positive for MRSA ST398. Meanwhile, the epidemiology of ST398 in Northern Europe appears to be shifting. Initially, all MRSA ST398 infections could be traced back to direct or indirect contact with livestock, but new cases without known livestock exposure are increasing, particularly in Denmark and the Netherlands. Yet, despite serious public health concerns, little is known about this rapidly emerging antibiotic-resistant pathogen. This is attributed in large part to the limitations of standard molecular analyses for elucidating the origins, evolution, and dispersal of the highly clonal ST398 lineage. To develop infection control and surveillance strategies, we must better understand the genomic changes that are facilitating the rapid emergence of MRSA ST398 and innovate more refined genotyping techniques to better characterize the reservoirs and transmission routes of human ST398 infection. In the current proposal, we will combine sequencing technologies with in vitro functional assays to assess the phylogenomic structure of ST398 (SA-1) and evaluate the genomic elements enabling human colonization and infection (SA-2, SA-3). We will further develop a set of high-resolution genotyping assays that can be applied in large- scale MRSA ST398 investigations (SA-4). To accomplish our proposed aims, we have assembled a highly qualified multi-national team: Dr. Price (PI; U.S.), an expert in environmental health, bacterial genomics, and translational research is uniquely qualified to lead this study; Dr. Keim (co-I; U.S.), a renowned expert in microbial genetics research will contribute to the genomics portion of this project, including the phylogenomics and assay development; Dr. Tara Smith (co-I; U.S.), a highly experienced American rural health researcher will conduct a longitudinal study of ST398 colonization and infection among U.S. farm workers; Drs. Robert Skov (co-I; Denmark) and Jan Kluytmans (co-I; the Netherlands), two clinician-scientists who have spearheaded the MRSA ST398 surveillance programs in their respective countries, will curate European ST398 isolate collections for the aims of this project. Key innovations of the current study include the application of phylogenomics to elucidate the MRSA ST398 sublineages and resolve the relative contribution of food-animal production on the emergence of this pathogen. Analyzing our unparalleled ST398 collections using a pan-genome approach will maximize our ability to discover genomic adaptations associated with human colonization and infection, as well as livestock-independent community dispersal. Successful completion of this project has the potential to immediately advance our understanding of an important antibiotic-resistant pathogen and facilitate our ability to mitigate its emergence.

描述（由申请人提供）：自 2004 年发现以来，与牲畜相关的 MRSA ST398 已成为北欧人类感染日益常见的原因，也是美国和世界各地牲畜和农场工人的普遍定植者。最近对爱荷华州养猪场的一项调查显示，70% 的养猪场以及近一半的养猪户的 MRSA ST398 呈阳性。与此同时，北欧 ST398 的流行病学似乎正在发生变化。最初，所有 MRSA ST398 感染均可追溯到与牲畜的直接或间接接触，但未知牲畜接触情况的新病例正在增加，特别是在丹麦和荷兰。然而，尽管存在严重的公共卫生问题，但人们对这种迅速出现的抗生素耐药性病原体知之甚少。这在很大程度上归因于标准分子分析在阐明高度克隆 ST398 谱系的起源、进化和传播方面的局限性。为了制定感染控制和监测策略，我们必须更好地了解促进 MRSA ST398 快速出现的基因组变化，并创新更精细的基因分型技术，以更好地表征人类 ST398 感染的储存库和传播途径。在当前的提案中，我们将结合测序技术和体外功能测定来评估 ST398 (SA-1) 的系统发育结构，并评估能够人类定植和感染的基因组元件 (SA-2、SA-3)。我们将进一步开发一套可应用于大规模 MRSA ST398 研究 (SA-4) 的高分辨率基因分型测定方法。为了实现我们提出的目标，我们组建了一支高素质的跨国团队：Price 博士（PI；美国），环境健康、细菌基因组学和转化研究方面的专家，具有领导这项研究的独特资格； Keim 博士（co-I；美国）是微生物遗传学研究领域的著名专家，他将为该项目的基因组学部分做出贡献，包括系统发育组学和检测开发；经验丰富的美国农村卫生研究员 Tara Smith 博士（co-I；美国）将对美国农场工人中 ST398 定植和感染进行纵向研究；博士。 Robert Skov（co-I；丹麦）和 Jan Kluytmans（co-I；荷兰）是两位在各自国家带头开展 MRSA ST398 监测计划的临床医生科学家，他们将为本项目的目的策划欧洲 ST398 分离物收集。当前研究的主要创新包括应用系统基因组学来阐明 MRSA ST398 亚系，并解决食用动物生产对该病原体出现的相对贡献。使用泛基因组方法分析我们无与伦比的 ST398 收藏品将最大限度地提高我们发现与人类殖民和感染以及不依赖牲畜的群落传播相关的基因组适应性的能力。该项目的成功完成有可能立即增进我们对重要的抗生素抗性病原体的了解，并提高我们减缓其出现的能力。