Genetic determinants of mycobacterial susceptibility and pathogenesis

当细菌进入宿主，如人或其他动物，它们通常被宿主的免疫系统检测到。然后，免疫反应试图杀死入侵的细菌。在大多数情况下，免疫反应是成功的。然而，在某些情况下，免疫反应不能杀死入侵者，入侵的细菌可以在宿主体内扎根和生长。当这种情况发生时，结果就是疾病。在包括结核病在内的许多疾病中，免疫反应并没有被细菌切断；相反，它是活跃的，但对杀死入侵者无效。在这些情况下，大多数疾病造成的损害不是由细菌直接引起的；相反，这种损伤是由这种无效的免疫反应引起的。这项提议的目的是了解致病细菌是如何逃脱免疫反应并在宿主体内扎根的，以及本应杀死入侵者的免疫反应是如何对宿主造成如此大的伤害的。为了研究这些问题，我们开发了一个新的系统来研究感染。在这个系统中，一种叫做海洋分枝杆菌的细菌被注射到果蝇（黑腹果蝇）体内，这种细菌与引起肺结核的细菌密切相关。这个系统非常有用，因为苍蝇和人类或牛等高等动物对细菌的大部分免疫反应是相似的。与此同时，我们对苍蝇了解很多，并且有很好的工具来研究它们，所以我们可以很容易地找到携带突变的苍蝇，这些突变使它们对抗这种感染的效率更高或更低，或者使感染对苍蝇的伤害更小。利用这些技术，我们可以找到对抵抗感染很重要的基因，或者是由于免疫反应而造成损害的基因。这些基因很难在高等生物（如老鼠）中找到，因为这个过程非常耗时，而且涉及到许多动物。例如，为了在老鼠身上做这个提议中的实验，将需要十多年的时间和一万多只老鼠。果蝇使我们能够快速而廉价地研究这些基因，而不存在使用老鼠或其他哺乳动物所固有的伦理问题。

When bacteria enter a host, such as a person or other animal, they are typically detected by the immune system of the host. The immune response then attempts to kill the invading bacteria. In most cases the immune response is successful. In some cases, though, the immune response fails to kill the invader, and the invading bacteria can become established and grow in the host. When this happens, disease is the result. In many diseases, including tuberculosis, the immune response is not shut off by the bacteria; instead, it is active, but ineffective at killing the invader. In these cases, most of the damage caused by the disease is not caused by the bacteria directly; rather, the damage is caused by this ineffective immune response. The goal of this proposal is to understand how disease-causing bacteria can escape the immune response and become established in the host, and how immune responses, which are supposed to just kill invaders, can instead come to cause so much damage to the host. In order to examine these issues, we developed a new system for the study of infection. In this system, a bacterium called Mycobacterium marinum, which is closely related to the bacterium that causes tuberculosis, is injected into a fruit-fly (Drosophila melanogaster). This system is very useful because much of the immune response to bacteria is similar between flies and higher animals, such as humans or cattle. At the same time, we know a great deal about flies, and have excellent tools for working with them, so that we can easily find flies with mutations that make them more- or less-efficient at fighting this infection, or mutations that make the infection less damaging to the fly. Using these techniques, we can find genes that are important for fighting infections or that cause the damage due to the immune response. These genes are difficult to find in higher organisms, such as mice, because the process is very time-consuming and involves many animals. For example, in order to do the experiments in this proposal in mice would take more than ten years and more than 10,000 mice. The fly allows us to study these genes rapidly and cheaply, without the ethical issues inherent in the use of mice or other mammals.