The importance of the intracellular energy metabolism of Salmonella Typhimurium within epithelial cells and macrophages

鼠伤寒沙门氏菌在上皮细胞和巨噬细胞内能量代谢的重要性

• 批准号: BB/J001007/1
• 负责人: Dave Kelly
• 金额: $ 3.42万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ001007%2F1
• 关键词: importance; intracellular; energy; metabolism; Salmonella

According to the latest European Food Standard Agency (EFSA) statistics (2008), Salmonella enterica serovar Typhimurium (S. Typhimurium) is the second most reported zoonotic infection in humans and the most frequent cause of food borne outbreaks in the EU. Worldwide Salmonella is responsible for up to 800,000 deaths from contaminated food and water. Following ingestion Salmonella bacteria travel to the intestine where they invade the cells lining the gut wall (epithelial cells), causing bloody diarrhoea. In the case of systemic infections (caused by S. Typhi and S. Paratyphi in humans), Salmonella invade the immune cells which are responsible for fighting infection (macrophages). Although the role of macrophages is to kill bacteria, Salmonella has adapted to evade the lethal chemical weapons deployed by macrophages. The Salmonella are able to survive and grow within the macrophages in a specialised compartment known as the 'Salmonella containing vacuole' (SCV), and thereby become systemically disseminated to other organs including the mesenteric lymph nodes, liver and spleen. We recently made the discovery that the major metabolic pathway required to catabolise sugars (glycolysis) is essential for the ability of Salmonella to grow and survive within macrophages, but not within epithelial cells. In order to grow and survive within host cells, Salmonella must also have a route for generating the energy required for these processes. Together with other evidence from our research, and published data, it seems likely that S. Typhimurium generates energy via different mechanisms in macrophages compared to epithelial cells. One of the aims of this proposal is to differentiate between these alternative energy generating pathways in macrophages and epithelial cells. Such information may facilitate therapeutic interventions. One of the major questions in infection biology is the extent to which the host cell contributes to the intracellular growth of Salmonella. We will use cutting edge techniques to determine the contribution of amino acids derived from host proteins and peptides to the intracellular growth of Salmonella in infected epithelial cells and macrophages. If Salmonella is dependent on the host for some of its requirements to enable intracellular growth, then this may also represent a way to facilitate therapeutic intervention.

根据最新的欧洲食品标准局（EFSA）统计数据（2008年），沙门氏菌血清鼠伤寒（S. typhimurium）是人类中第二大的人畜共患感染，也是欧盟最常见的食品繁殖原因。全球沙门氏菌可导致污染的食物和水最多80万人死亡。摄入后，沙门氏菌进入肠道，在那里它们侵入肠壁上的细胞（上皮细胞），引起血腥的腹泻。在全身感染（由人类的链球菌和副链球菌引起）的情况下，沙门氏菌会侵入负责对抗感染（巨噬细胞）的免疫细胞。尽管巨噬细胞的作用是杀死细菌，但沙门氏菌已适应逃避巨噬细胞部署的致命化学武器。沙门氏菌能够在称为“含液泡沙门氏菌”（SCV）的专门室内生存并生长在巨噬细胞中，从而在包括肠系膜淋巴结，肝脏和脾脏（包括肠系膜淋巴结）上系统地被系统地传播到其他器官中。我们最近发现，分解代谢性糖（糖酵解）所需的主要代谢途径对于沙门氏菌在巨噬细胞中生长和生存的能力至关重要，而不是在上皮细胞中。为了在宿主细胞中生长和生存，沙门氏菌还必须具有产生这些过程所需的能量的途径。与我们的研究中的其他证据以及发布的数据一起，与上皮细胞相比，鼠伤寒链球菌似乎通过巨噬细胞的不同机制产生能量。该建议的目的之一是区分巨噬细胞和上皮细胞中的这些替代能量产生途径。这些信息可能有助于治疗干预措施。感染生物学的主要问题之一是宿主细胞在多大程度上有助于沙门氏菌的细胞内生长。我们将使用尖端技术来确定源自宿主蛋白和肽对感染上皮细胞和巨噬细胞中沙门氏菌细胞内生长的氨基酸的贡献。如果沙门氏菌取决于宿主的某些要求以实现细胞内生长，那么这也可能代表了一种促进治疗干预的方法。

项目成果

A Comparison of the ATP Generating Pathways Used by S. Typhimurium to Fuel Replication within Human and Murine Macrophage and Epithelial Cell Lines.

• DOI: 10.1371/journal.pone.0150687
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Garcia-Gutierrez E;Chidlaw AC;Le Gall G;Bowden SD;Tedin K;Kelly DJ;Thompson A
• 通讯作者: Thompson A