Importance of the intracellular energy metabolism of S. Typhimurium within epithelial cells and macrophages

根据欧洲食品标准局（EFSA）的最新统计数据（2008年），鼠伤寒沙门氏菌（S. Typhimurium）是欧盟报告的第二大人畜共患感染，也是最常见的食源性暴发原因。全世界有80万人死于受污染的食物和水，沙门氏菌是罪魁祸首。食用后沙门氏菌进入肠道，侵入肠壁的细胞（上皮细胞），引起血性腹泻。在全身性感染（由人类伤寒沙门氏菌和副伤寒沙门氏菌引起）的情况下，沙门氏菌侵入负责抵抗感染的免疫细胞（巨噬细胞）。虽然巨噬细胞的作用是杀死细菌，但沙门氏菌已经适应了逃避巨噬细胞部署的致命化学武器。沙门氏菌能够在巨噬细胞中存活并生长在一个被称为“含沙门氏菌液泡”（SCV）的特殊隔室中，从而全身扩散到其他器官，包括肠系膜淋巴结、肝脏和脾脏。我们最近发现，分解糖（糖酵解）所需的主要代谢途径对沙门氏菌在巨噬细胞内生长和存活的能力至关重要，但在上皮细胞内却不是。为了在宿主细胞内生长和存活，沙门氏菌也必须有一种途径来产生这些过程所需的能量。结合我们研究的其他证据和已发表的数据，与上皮细胞相比，鼠伤寒沙门氏菌在巨噬细胞中产生能量的机制似乎不同。该建议的目的之一是区分巨噬细胞和上皮细胞中这些可替代的能量产生途径。这些信息可能有助于治疗干预。感染生物学中的一个主要问题是宿主细胞在多大程度上促进了沙门氏菌的细胞内生长。我们将使用尖端技术来确定从宿主蛋白和肽中提取的氨基酸对感染上皮细胞和巨噬细胞中沙门氏菌胞内生长的贡献。如果沙门氏菌依赖宿主来满足其细胞内生长的某些需求，那么这也可能是促进治疗干预的一种方法。

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.