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）：社区相关金黄色葡萄球菌（CA-SA），例如美国流行的耐甲氧西林菌株 USA300，在过去十年中导致皮肤和软组织感染急剧增加。其中一些感染也是侵入性的，通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，尽管我们对其如何在社区中传播和持续存在的了解有限。菌株很可能会对其环境进行微小的基因改造，从而变得更加“适应”生态。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，我们获得了随时间推移离散遗传适应的原理证明。与此同时，最初的人畜共患菌株 ST398 MSSA 似乎正在曼哈顿北部出现，没有任何动物接触。它现在是我们临床感染性 MSSA 分离株中最流行的菌株之一，具有显着的人际传播能力，并且在定植环境家庭表面上表现出更高的存活率。本研究的总体目标是，以已确立的流行性 USA300 和不断发展的人畜共患菌株 ST398 为例，通过使用组合流行病学和遗传学方法。具体而言，本提案的目的是 (1) 确定 USA300 近期基因变化对金黄色葡萄球菌适应性和环境适应的功能影响，(2) 确定曼哈顿北部 ST398 的储存库和传播模式，以及 (3 ）确定猪菌株 ST398 如何进化为人类病原体。我们将首先研究后来测序的 USA300 突变的体外适应性、存活率和细胞粘附特性，我们假设这些突变改变了这些菌株的适应性和存活率。然后，我们将把我们的研究扩展到新兴的 ST398，以确定其在北曼哈顿的传播基础。基于集群设计，我们将采访和培养 ST398 阳性受试者、他们的接触者以及接触者的接触者，以确定与 ST398 获得和传播相关的因素。至关重要的是，这些研究将为比较测序提供样本，并允许比较人类定植菌株、感染菌株以及持久性和非持久性菌株。将在 USA300 研究中实施的功能测定中研究同基因突变体的序列差异。我们预计这项工作将导致确定 ST398 在人与人之间直接传播的遗传特征，并有助于增强适应性和生态适应。这项研究与我成为金黄色葡萄球菌发病机制领域的独立医师研究员的目标直接一致。 金黄色葡萄球菌等细菌可能会导致社区中原本健康的年轻人感染。我们对这些细菌如何传播以及它们为何持续存在的了解有限。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来限制它们的传播。