Mechanisms of S. aureus transmission and persistence.

金黄色葡萄球菌传播和持久性的机制。

• 批准号: 8288354
• 负责人: Anne-Catrin Uhlemann
• 金额: $ 13.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288354
• 关键词: Accounting; Address; Adhesions; Adopted; Affect; Animals; Athletic; Bacteria; Biological Assay; Canada; Cell Adhesion; Characteristics; Child; Clinical; Collection; Communities; Deletion Mutation; Deltastab; Disease; Disease Outbreaks; Dominican Republic; Engineering; Environment; Epidemic; Epidemiologic Studies; Epidemiology; Europe; European; Event; Evolution; Family member; Family suidae; Fatal Outcome; Friends; Gene Mutation; Genes; Genetic; Genome; Goals; Growth; Household; Human; In Vitro; Individual; Infection; Interview; Knowledge; Lead; Measures; Methicillin; Methicillin Resistance; Minor; Mobile Genetic Elements; Modification; Molecular; Mutate; Mutation; Netherlands; Nose; Pathogenesis; Persons; Physicians; Population; Prisons; Property; Recruitment Activity; Research; Research Design; Research Personnel; Risk Factors; Sampling; Site; Site-Directed Mutagenesis; Skin Tissue; Soft Tissue Infections; Sports; Squamous Epithelium; Staphylococcus aureus; Surface; Techniques; Time; Tissues; United States; Virulence; Work; base; comparative; design; environmental adaptation; fitness; genetic analysis; genetic evolution; indexing; interest; member; methicillin resistant Staphylococcus aureus; mutant; novel; pathogen; prevent; research study; resistant strain; soft tissue; success; therapy design; trait; transmission process

DESCRIPTION (provided by applicant): Community-associated Staphylococcus aureus (CA-SA), such as USA300, the epidemic methicillin-resistant strain in the US, have led to a dramatic increase of skin and soft tissues infections over the past decade. Some of these infections are also invasive and often occur in otherwise healthy individuals. CA-SA appear to posses an enhanced capacity for both transmission and invasion, though we have limited understanding of how they spread and persist in the community. It is likely that strains adapt with minor genetic modifications to their environment and become more ecologically "fit". We have obtained proof of principle of discrete genetic adaptations over time by sequencing closely related USA300 strains, longitudinally collected from the same households. Concurrently, it appears that the originally zoonotic strain ST398 MSSA is emerging in the Northern Manhattan, without any animal contact. It is now amongst the most prevalent strains of our clinical infectious MSSA isolates, has a remarkable ability to spread from person-to-person, and shows enhanced survival on colonized environmental household surfaces. The overall goal of this study is to define the mechanisms of transmission and persistence of successful S. aureus strains as they adapt to their environmental niches, taking the examples of the well- established epidemic USA300 and the evolving zoonotic strain ST398, by using a combined epidemiologic and genetic approach. Specifically, the aims of this proposal are to (1) define the functional impact on S. aureus fitness and environmental adaptation of recent genetic changes in USA300, (2) define the reservoirs and modes of transmission of ST398 in Northern Manhattan, and (3) determine how the pig strain ST398 has evolved as a human pathogen. We will first study in vitro fitness, survival and cell adhesion properties of mutations of the sequenced later USA300, that we hypothesized have altered the fitness and survival of these strains. We will then extend our studies to the emerging ST398 to define the basis of its transmission in Northern Manhatten. Based on a cluster-based design we will interview and culture ST398 positive subjects, their contacts and contacts of contacts to determine factors associated with acquisition and spread of ST398. Critically, these studies will provide samples for comparative sequencing and will allow for comparison of human colonizing strains, infectious strains, as well as persisting and non-persisting strains. Sequence differences will be studied on isogenic mutants in functional assays implemented in studies on USA300. We anticipate that this work will lead to the identification of genetic traits accounting for the direct person-to-person transmission of ST398 and that contribute to enhanced fitness and ecological adaptation. This research is in direct line with my goal of becoming an independent Physician-investigator in the field of S. aureus pathogenesis. Bacteria such as Staphylococcus aureus can cause infections in otherwise healthy young people in the community. We have limited understanding of how these bacteria spread and why they persist. This research will help to find out how some of these strains survive and enable us to design interventions to limit their spread.

描述（由申请人提供）：在美国，与社区相关的金黄色葡萄球菌（CA-SA），例如USA300，在美国流行甲氧西林抗性菌株，导致了过去十年中皮肤和软组织感染的急剧增加。其中一些感染也具有侵入性，并且经常发生在其他健康的个体中。 CA-SA似乎具有增强的传播和入侵能力，尽管我们对它们如何在社区中的传播和持续存在有限。菌株可能会适应其环境的较小遗传修饰，并在生态上变得更加“拟合”。我们通过对从同一家庭纵向收集的密切相关的USA300菌株进行测序，通过对密切相关的USA300菌株进行测序，获得了离散遗传适应原理的证明。同时，看来最初是人畜共患菌株ST398 MSSA正在曼哈顿北部出现，没有任何动物接触。现在，它是我们临床感染性MSSA分离株中最普遍的菌株之一，具有显着的从人与人之间传播的能力，并且显示出殖民地环境家庭表面的生存增强。这项研究的总体目的是通过使用一种相结合的流行病学方法和遗传学方法来定义其适应环境壁ni的成功链球菌菌株的传播和持久性的机制，以它们适应环境壁nikes的态度。具体而言，该提案的目的是（1）定义对金黄色葡萄球菌的适应性和环境适应USA300遗传变化的功能影响，（（2）定义曼哈顿北部ST398的储层和传播模式，以及（3）确定Pig Plain ST398如何发展为人类途径。我们将首先研究测序后期的USA300突变的体外适应性，存活和细胞粘附特性，我们假设已经改变了这些菌株的适应性和存活。然后，我们将把研究扩展到新兴的ST398，以定义其在曼哈顿北部传播的基础。基于基于群集的设计，我们将采访和培养ST398积极对象，他们的联系和联系人的联系，以确定与获得和ST398的获取和传播相关的因素。至关重要的是，这些研究将为比较测序提供样本，并可以比较人类定植菌株，传染性菌株以及持续和非固定菌株。在USA300研究中实施的功能测定中，将研究序列差异。我们预计，这项工作将导致识别遗传特征，这些遗传特征是ST398的直接人对人的直接传播，这有助于增强健康和生态适应。这项研究与我成为金黄色葡萄球菌发病机理领域的独立医师评估剂的目标是直接的。 金黄色葡萄球菌等细菌会引起社区中健康的年轻人的感染。我们对这些细菌的传播方式以及为什么持续存在的理解有限。这项研究将有助于找出其中一些菌株如何生存并使我们能够设计干预措施以限制其传播。