The Interplay between Immune Cells and Staphylococcus aureus in Kidney Infections

金黄色葡萄球菌（S.）是一种细菌，主要寄生于约30%的健康人群的皮肤和粘膜，但可以引起一些感染，例如皮肤感染，在正常情况下很容易由免疫系统控制。尽管如此，金黄色葡萄球菌可引起严重的危及生命的全身性感染，通常是由于导管等血管通路装置或皮肤脓肿破裂所致。此外，这种细菌对抗生素的耐药性越来越强，给患者的治疗带来了更多困难。通常，全身金黄色葡萄球菌感染导致器官衰竭和肾脏通常受到影响。肾脏是一个非常重要的器官，它由不同的解剖结构和不同的细胞类型组成，以维持其功能，例如排泄废物，这可能在感染期间受到影响。但是，金黄色葡萄球菌感染会影响肾脏的哪个部位和哪些细胞，以及细菌是如何进入肾脏的，这些都是完全未知的。吞噬细胞——中性粒细胞和单核细胞/巨噬细胞——主要是免疫系统消灭细菌的第一批细胞。因此，更详细地研究这些细胞与金黄色葡萄球菌之间的相互作用及其在病原体传播到肾脏中的作用是非常有意义的。在系统性金黄色葡萄球菌感染期间，大多数细菌被肝脏巨噬细胞捕获并消灭，然而，大约10%的细菌能够克服这种免疫机制并扩散到其他器官，特别是肾脏。一种可能性是，一旦细菌从肝巨噬细胞中逃逸出来，它们就会被中性粒细胞识别，并在这些细胞中以特洛伊木马的形式通过血液输送到其他器官。腹腔巨噬细胞是一种可以渗透到内脏器官的细胞类型，它为金黄色葡萄球菌传播到肾脏提供了第二种可能性，因为我的初步数据显示，在系统性金黄色葡萄球菌感染中，细菌也在腹腔中生长。本提案的主要目的是研究金黄色葡萄球菌如何传播到肾脏以及中性粒细胞和巨噬细胞在这一过程中发挥的作用。一个已经建立的全身金黄色葡萄球菌感染的小鼠模型结合双光子活体显微镜将显示细菌在什么时间点到达肾脏的哪个区域。不同的报告或敲除小鼠将提供有关免疫细胞贡献的信息。该项目将为系统性和肾脏金黄色葡萄球菌感染的发病机制提供新的见解，并确定肾脏的传播机制，为调节免疫过程提供新的治疗选择。了解金黄色葡萄球菌肾脏感染是如何发生的，对于开发能够预防这一过程并拯救患者免于器官衰竭的药物非常重要。

Staphylococcus (S.) aureus is a bacterium that colonizes mostly the skin and mucosae of around 30 % of the healthy population but can cause some infection for example of the skin, which can easily be managed by the immune system under normal conditions. Albeit, S. aureus can cause severe life-threatening systemic infections often due to vascular access devices as catheters or rupture of skin abscesses. Additionally, the bacterium is developing more and more resistance against antibiotics resulting in more difficulties in patients´ treatment. Frequently, systemic S. aureus infectious result in organ failure and the kidneys are commonly affected. The kidney is a very important organ that is comprised of different anatomical structures with different cell types to maintain functions as e.g. the excretion of waste, which can be affected during infections. But which part of the kidneys and which cells are affected in S. aureus infections as well as how the bacteria entering the kidneys is completely unknow. Phagocytes – neutrophils and monocytes/macrophages – are mainly the first cells of the immune systems that eliminate bacteria. Therefore, it is of great interest to investigate the interplay between these cells with S. aureus and their role in dissemination of the pathogen to the kidneys in more detail. During systemic S. aureus infections, most bacteria are getting caught and eliminated by liver macrophages, however, around 10 % are able to overcome that immune mechanism and spread to other organs, especially the kidneys. One possibility is that as soon as the bacteria escape from liver macrophages they are recognized by neutrophils and transported in these cells in a Trojan Horse via the blood stream to other organs. Macrophages in the peritoneal cavity, a cell type that can infiltrate inner organs, present a second possibility for dissemination of S. aureus to the kidneys, as my preliminary data show that in systemic S. aureus infections the bacteria also grow in the peritoneal cavity.The main aim of this proposal is to investigate how S. aureus disseminates to the kidneys and which role neutrophils and macrophages play in this process. An already established mouse model of systemic S. aureus infection in combination with 2-photon intravital microscopy will show in vivo at what time point bacteria arrive in which areas of the kidneys. Different reporter or knock out mice will provide information about the contribution of immune cells. This project will provide new insights into the pathogenesis of systemic and renal S. aureus infections and identify dissemination mechanisms to the kidney that constitute a basis for modulation of immunological processes leading to new options for therapy. It is important to understand how Staphylococcus aureus kidney infections occurs to develop drugs that can prevent this process and save patients from organ failure.