A mathematical and biophysical analysis of salmonella macrophage interactions

肠道沙门氏菌在许多动物中引起广泛的疾病。沙门氏菌感染给养殖业造成的经济损失可能非常大，但同样重要的是，感染动物的一些血清型也会导致人类食物中毒和胃肠炎。沙门氏菌感染特殊的免疫细胞(巨噬细胞)，细菌驻留在称为含有沙门氏菌的空泡的细胞内。在巨噬细胞内，细菌可能被杀死，可能隐藏，可能生长，并可能导致细胞死亡。巨噬细胞和沙门氏菌之间的相互作用对疾病的发展至关重要。控制巨噬细胞内的细菌数量是使宿主阻止细菌生长并在感染中存活的重要步骤。沙门氏菌与巨噬细胞相互作用的许多机制尚不清楚。特别是，人们对巨噬细胞与细胞的物理相互作用知之甚少。巨噬细胞通过称为模式识别受体(PRRs)的特殊蛋白质来检测细菌的存在，这种蛋白质诱导巨噬细胞反应，帮助宿主控制沙门氏菌感染。在这个项目中，我将使用数学模型来预测PRR活性如何影响沙门氏菌感染巨噬细胞的过程，然后使用生物学实验来检验这些理论假设。我将使用物理技术来研究PRRs是否影响沙门氏菌与巨噬细胞的结合。在项目的最后部分，我将比较PRR活性如何影响巨噬细胞对感染的全球反应。这个项目将增加我们对沙门氏菌如何感染巨噬细胞的了解，并可能为开发治疗这些病原体引起的疾病的药物提供新的靶点。

Salmonella enterica causes a wide range of diseases in many animals. Economic losses to the farming industry through Salmonella infection are potentially very high, but also important is the fact that a number of serovars that infect animals can also cause food poisoning and gastroenteritis in humans. Salmonella infect specialised immune cells (macrophages) where the bacteria reside within an intracellular compartment called the salmonella-containing vacuole. Within the macrophage the bacteria may be killed, may hide, may grow and can cause the cell to die. The interaction between macrophages and salmonellae is critically important to the progression of disease. Controlling the numbers of bacteria within the macrophage is an important step in enabling the host to stop the bacteria growing and to survive infection. Many mechanisms involved in the interaction between Salmonella and macrophages are unclear. In particular little is known about how the macrophage physically interacts with the cell. The macrophage detects the presence of bacteria through specialised proteins called Pattern Recognition Receptors (PRRs) which induce macrophage responses to help the host control a salmonella infection. In this project I will use mathematical models to predict how PRR activity effects the process by which Salmonella infect macrophages and then test these theoretical assumptions using biological experiments. I will use physical techniques to investigate whether PRRs influence how Salmonella associate with macrophages. In the final part of the project I will compare how PRR activity affects the global response of macrophages to infection. This project will increase our understanding of how Salmonella infect macrophages and may deliver new targets for developing drugs to treat the diseases caused by these pathogens.