The role of commensal organisms as pro-infectious agents in Staphylococcus aureus infection dynamics.

金黄色葡萄球菌是一种重要的人类病原体，在世界各地引起重大死亡和疾病。耐甲氧西林沙门氏菌等耐抗生素菌株的传播加剧了这一问题。金黄色葡萄球菌（MRSA）。MRSA通常是一种医院相关感染，但最近社区获得性MRSA在明显缺乏抗生素选择的情况下有所增加。因此，有一个不断的需要，以发展新的控制制度，S。金黄色葡萄球菌，因为这种微生物已经开始显示耐药性，甚至对新的抗生素，如利奈唑胺和没有疫苗可用。为了赢得这场战斗，我们不仅要开发新的治疗方法和预防措施，还要了解S。金黄色葡萄球菌引起疾病，因此如何最好地利用干预措施，以减少疾病负担，并尽量减少对抗生素耐药性的发展和传播。人类是如何感染S. aureus？我们有一个惊人的发现，相对无害的皮肤微生物，甚至它们的细胞壁成分，都能引起沙门氏菌的严重恶化。金黄色葡萄球菌感染，使疾病发生的感染剂量大大减少。人类感染的最常见途径是通过伤口，当然，这将发生与任何材料进入，包括S。金黄色。我们已经命名了能增加S的物质。金黄色葡萄球菌感染作为“促感染剂”。我们已经打开了一扇关于自然感染的窗户，并在这样做的过程中提供了新的途径，试图了解疾病，以及我们如何可以预防它。目前的应用需要一个跨学科的方法来了解感染是如何开始的，可以作为促感染剂的材料和生物体的性质，感染如何进展，以及如何利用这些知识来预防和/或治疗疾病。我们的背景工作和建议需要一个由微生物学家和具有先天免疫研究专长的临床医生领导的综合团队。我们的专业知识与世界各地的重要合作伙伴相结合，为我们雄心勃勃的计划提供了可靠的网络支持。我们的工作得到了动物感染模型的支持，因为如果不了解体内发生的情况，就无法在体外重现这一复杂的过程。我们已经独特地开发了脊椎动物斑马鱼胚胎作为S。金黄色葡萄球菌全身性疾病这提供了一种高通量、遗传上易处理的系统，其中可以在活宿主中观察到宿主：病原体相互作用。该模型的重要性在于，它不仅提供了对发病机制的重要见解，而且还为我们使用哺乳动物系统提供了信息，从而直接取代了许多小鼠实验，减少了使用的哺乳动物数量并改进了我们的方法。我们将使用动物模型的组合，以及体外分析，以确定可以增加S的材料的宽度。金黄色葡萄球菌感染和这种作用的细胞和分子机制。然后将绘制从感染开始到终点的感染图，以确定瓶颈，作为开发新干预策略的位点。我们将在所有模型中使用各种方法，包括最先进的活体显微镜，以确定感染途径。该应用程序提供了一个集成包，将进一步加深我们对疾病机制的理解，以及如何使用这些信息为临床实践提供信息。

Staphylococcus aureus is an important human pathogen that causes significant death and disease around the world. The problem is exacerbated by the spread of antibiotic resistant strains such as Methicillin Resistant S. aureus (MRSA). MRSA is generally a hospital-associated infection but recently community acquired MRSA has increased in the apparent absence of antibiotic selection. Thus there is a constant need to develop new control regimes for S. aureus, as this organism has begun to show resistance even to new antibiotics such as linezolid and no vaccine is available. To win this battle we must not only produce new treatments and preventative measures but also to understand the complexities of how S. aureus causes disease and thus how interventions can be best utilised, to reduce the disease burden and to minimise the development and spread of resistance to antibiotics. How do humans get infected with S. aureus? We have made the astonishing discovery that relatively harmless skin organisms and even their component cell walls are able to cause significant exacerbation of S. aureus infection, allowing disease to occur with a hugely reduced infectious dose. The most common route of human infection is via a wound and of course this will occur with whatever material gets in, including S. aureus. We have named the material that can augment S. aureus infection as "pro-infectious agents". We have opened a window on natural infection and in doing so provide novel avenues for trying to understand disease and how we may prevent it. The current application takes an interdisciplinary approach to understand how infection is initiated, the nature of material and organisms that can act as pro-infectious agents, how infection progresses and how such knowledge may be utilized to prevent and/or cure disease. Our background work and that proposed necessitates an integrated team led by a microbiologist and a clinician with research expertise in innate immunity. This combined expertise, coupled with important partners around the world, provides a proven network to underpin our ambitious proposal.Our work is underpinned by the use of animal models of infection, as this complex process cannot be recapitulated in vitro without understanding of what happens in vivo. We have uniquely developed the vertebrate zebrafish embryo as a model of S. aureus systemic disease. This provides a high-throughput, genetically tractable system where host:pathogen interaction can be observed in a living host. The importance of this model is that it has not only provided important insights into pathogenesis but has also informed our use of a mammalian system thus replacing many mouse experiments directly, reducing the numbers of mammals used and refining our approach. We will use a combination of animal models, together with in vitro analysis to determine the breadth of material that can augment S. aureus infection and the cellular and molecular mechanisms underlying this effect. Infection will then be mapped from initiation to endpoint in order to identify bottlenecks as sites for the development on novel intervention strategies. We will use a variety of approaches including state-of-the-art intravital microscopy in all models to determine the pathway of infection.The application provides an integrated package that will further our understanding of disease mechanisms and how this information may be used to inform clinical practice.