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

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的日益常见的原因，也是美国和世界各地牲畜和农场工人的普遍殖民者。最近对爱荷华州养猪场的一项调查显示，70%的养猪场——近一半的养猪户——对MRSA ST398呈阳性反应。与此同时，ST398在北欧的流行病学似乎正在发生变化。最初，所有MRSA ST398感染都可以追溯到与牲畜的直接或间接接触，但没有已知与牲畜接触的新病例正在增加，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耐抗生素病原体知之甚少。这在很大程度上归因于标准分子分析在阐明ST398高克隆谱系的起源、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。在目前的提案中，我们将结合测序技术和体外功能分析来评估ST398 （SA-1）的系统基因组结构，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用于大规模MRSA ST398调查（SA-4）的高分辨率基因分型检测方法。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，是唯一有资格领导这项研究的人；Keim博士（co-I； U.S.）是微生物遗传学研究领域的知名专家，他将为该项目的基因组学部分做出贡献，包括系统基因组学和分析开发；Tara Smith博士（co-I； U.S.），一位经验丰富的美国农村卫生研究员将在美国农场工人中进行ST398定植和感染的纵向研究；Drs。Robert Skov（丹麦）和Jan Kluytmans（荷兰），两位在各自国家率先开展MRSA ST398监测项目的临床科学家，将为该项目的目标策划欧洲ST398分离物收集。当前研究的关键创新包括应用系统基因组学来阐明MRSA ST398亚谱系，并解决食品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集合将最大限度地提高我们发现与人类殖民和感染相关的基因组适应性，以及家畜独立的群落扩散的能力。这个项目的成功完成有可能立即促进我们对一种重要的抗生素耐药病原体的了解，并促进我们减轻其出现的能力。

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.