The Interplay between Immune Cells and Staphylococcus aureus in Kidney Infections

肾脏感染中免疫细胞和金黄色葡萄球菌之间的相互作用

• 批准号: 390018950
• 负责人: Dr. Selina Kathleen Jorch
• 金额: --
• 依托单位: Department of Physiology and Pharmacology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390018950?language=en
• 关键词: Interplay; between; Immune; Cells; Staphylococcus

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.

金黄色葡萄球菌 (S.) 金黄色葡萄球菌是一种细菌，主要定殖在约 30% 健康人群的皮肤和粘膜上，但也可能引起一些感染，例如皮肤感染，而在正常情况下，免疫系统可以轻松控制这种感染。尽管如此，金黄色葡萄球菌仍可引起严重危及生命的全身感染，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，细菌对抗生素的耐药性越来越强，给患者的治疗带来更多困难。通常，全身性金黄色葡萄球菌感染会导致器官衰竭，并且肾脏通常会受到影响。肾脏是一个非常重要的器官，由不同的解剖结构和不同的细胞类型组成，以维持功能，例如肾脏。废物的排泄，在感染期间可能会受到影响。但金黄色葡萄球菌感染影响肾脏的哪一部分和哪些细胞，以及细菌如何进入肾脏，目前还完全未知。吞噬细胞（中性粒细胞和单核细胞/巨噬细胞）主要是免疫系统中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非常有意义。在全身性金黄色葡萄球菌感染期间，大多数细菌会被肝脏巨噬细胞捕获并消除，但大约 10% 的细菌能够克服这种免疫机制并扩散到其他器官，尤其是肾脏。一种可能性是，细菌一旦从肝脏巨噬细胞中逸出，就会被中性粒细胞识别，并以特洛伊木马的方式在这些细胞中通过血流运输到其他器官。腹膜腔中的巨噬细胞是一种可以浸润内部器官的细胞类型，为金黄色葡萄球菌传播到肾脏提供了第二种可能性，因为我的初步数据表明，在全身性金黄色葡萄球菌感染中，细菌也在腹膜腔中生长。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的作用 在这个过程中发挥。已经建立的全身性金黄色葡萄球菌感染小鼠模型与 2 光子活体显微镜相结合，将在体内显示细菌在什么时间点到达肾脏的哪些区域。不同的报告小鼠或基因敲除小鼠将提供有关免疫细胞贡献的信息。该项目将为全身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，这构成了调节免疫过程的基础，从而产生新的治疗选择。重要的是要了解金黄色葡萄球菌肾脏感染是如何发生的，以开发可以阻止这一过程并挽救患者免于器官衰竭的药物。

项目成果

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis.

• DOI: 10.1016/j.chom.2018.06.017
• 发表时间: 2018-08-08
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Surewaard BGJ;Thanabalasuriar A;Zeng Z;Tkaczyk C;Cohen TS;Bardoel BW;Jorch SK;Deppermann C;Bubeck Wardenburg J;Davis RP;Jenne CN;Stover KC;Sellman BR;Kubes P
• 通讯作者: Kubes P