Mechanisms of S. aureus transmission and persistence.

描述（由申请人提供）：社区相关金黄色葡萄球菌（CA-SA），如USA 300，美国流行的耐甲氧西林菌株，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似乎增强了传播和入侵的能力，尽管我们对它们如何在社区中传播和持续存在的了解有限。很可能是菌株通过微小的遗传修饰适应环境，变得更加“适合”生态。我们通过对从相同家庭纵向收集的密切相关的USA 300菌株进行测序，获得了随时间推移离散遗传适应的原则证据。同时，最初的人畜共患病菌株ST 398 MSSA似乎正在北方曼哈顿出现，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，具有在人与人之间传播的显著能力，并在定植的环境家庭表面上显示出增强的存活率。本研究的总体目标是确定成功的S。金黄色葡萄球菌菌株，因为他们适应他们的环境生态位，采取了良好的流行USA 300和不断发展的人畜共患病菌株ST 398的例子，通过使用流行病学和遗传学相结合的方法。具体而言，本建议的目的是（1）定义对S的功能影响。金黄色葡萄球菌适应性和环境适应性的研究，（2）确定ST 398在北方曼哈顿的宿主和传播方式，（3）确定猪株ST 398如何演变为人类病原体。我们将首先研究体外健身，生存和细胞粘附特性的突变测序后USA 300，我们假设已经改变了健身和生存这些菌株。然后，我们将扩展我们的研究，以新兴的ST 398，以确定其在北方曼哈顿的传播基础。基于聚类设计，我们将采访和文化ST 398阳性的主题，他们的接触和接触的接触，以确定与ST 398的获得和传播的相关因素。重要的是，这些研究将提供用于比较测序的样本，并将允许比较人类定殖菌株、感染性菌株以及持续性和非持续性菌株。将在USA 300研究中实施的功能试验中研究同基因突变体的序列差异。我们预计，这项工作将导致识别的遗传性状占ST 398的直接人传人，并有助于增强健身和生态适应。这项研究与我成为S.金黄色葡萄球菌致病性。 金黄色葡萄球菌等细菌可能会导致社区中健康的年轻人感染。我们对这些细菌如何传播以及它们为什么持续存在的了解有限。这项研究将有助于找出这些菌株是如何生存的，并使我们能够设计干预措施来限制它们的传播。

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.