Do post-receptor binding events decide the fate of mycobacteria in bovine macrophages?

牛结核病是由牛分枝杆菌(M.bovis)引起的一种牛疾病，除了经济上的影响外，它还会对动物福利造成严重的后果。在英国，尽管采取了控制措施，但牛结核病病例的数量仍在继续增加。与皮试相比，接种疫苗可能是一种更好的控制手段。皮试目前用于识别受感染的牛，必须将其销毁以防止疾病传播。卡介苗(源于牛分枝杆菌)目前用于人类抗结核病，并已被测试其在预防牛结核病方面的适宜性。与人类一样，在牛身上使用卡介苗已被证明对疾病具有部分保护作用。目前，卡介苗是最好的结核病疫苗，但我们并不完全理解为什么感染牛型支原体会导致疾病，感染卡介苗则会产生保护作用。有趣的是，引起人类结核病的结核杆菌不会引起牛的疾病，而牛分枝杆菌能够引起牛和人的结核病。抗原提呈细胞(APC)是人体内部防御系统(免疫系统)中第一个与致病细菌(病原体)接触的细胞。APC负责启动免疫系统对控制和消除病原体的反应。病原体是由APC通过其表面的特殊分子识别的，这种分子被称为模式识别受体，在免疫反应的发展中发挥着至关重要的作用。然而，分枝杆菌能够影响APC的反应，因此APC的防御机制不是杀死病原体，而是改变--允许细菌生存、繁殖并继续致病。APC和分枝杆菌之间的相互作用触发了一系列事件，称为信号级联反应，导致决定APC是否会启动保护性反应或允许疾病进展的分子的表达。这项建议旨在研究一种主要的APC，称为肺泡巨噬细胞。该细胞驻留在肺部，是第一批通过呼吸道途径与侵入人体的细菌接触的APC之一。我们将研究这种牛细胞如何与引起结核病的牛分支杆菌(它也会导致人类结核病)、卡介苗(疫苗菌株)和结核分支杆菌(它会导致人类而不是牛)相互作用。通过比较细胞对三种不同细菌的反应，我们的目标是识别肺泡巨噬细胞的反应，只有引起结核病的牛分支杆菌才能看到。这将使我们能够识别免疫反应的各个阶段，如果细菌随后将导致疾病而不是免疫，就像卡介苗和结核分枝杆菌在牛身上所看到的那样，特定反应是关键的。这一建议旨在验证这样一种假设，即牛分枝杆菌通过特定的模式识别受体的使用和对影响免疫反应结果的信号级联的干扰，确保其在牛肺泡巨噬细胞内的存活，从而确保疾病的进展。这与卡介苗或结核分枝杆菌使用的受体和激活的信号级联反应形成对比，后者导致感染细胞分泌特定分子，导致免疫而不是活动性疾病。我们认为，牛分枝杆菌(包括牛和人)和结核分枝杆菌(仅限于人类)宿主特异性的差异，以及牛分枝杆菌(引起结核病)和卡介苗(没有疾病，可以发展免疫)在牛肺泡巨噬细胞中的毒力(致病能力)是细胞反应和随后的细菌杀灭的关键，因此对暴露于分枝杆菌的结果至关重要。更好地理解牛肺泡巨噬细胞中导致保护性免疫或允许疾病发展的机制对于开发新的治疗方法和疫苗非常重要。

Bovine tuberculosis (TB) is a disease of cattle caused by the bacterium Mycobacterium bovis (M.bovis), which has severe consequences for animal welfare in addition to financial implications. In the UK, the number of cases of bovine TB continues to increase, despite the application of control measures. Vaccination may be a better means of control, compared to the skin test that is currently used to identify infected cattle which have to be destroyed to prevent spread of disease. The vaccine BCG (derived from M.bovis) is currently used against TB in humans, and has been tested for its suitability in preventing bovine TB. As in humans, BCG use in cattle has been shown to be partially protective against disease. At present, BCG is the best vaccine against TB, but we do not completely understand why infection with M.bovis results in disease and infection with BCG results in protection. Interestingly, M.tuberculosis, which causes TB in humans, does not cause disease in cattle, while M.bovis is able to cause TB in cattle and humans. Antigen presenting cells (APC) are the first cells of the body's internal defence system (the immune system) to come into contact with disease-causing bacteria (pathogens). APC are responsible for the onset of the response of the immune system towards controlling and eliminating pathogens. Pathogens are recognised by APC through special molecules on their surface, known as pattern recognition receptors, which play a vital role in the development of the immune response. However, mycobacteria are able to influence the response of APC, so rather than killing the pathogen the APC's defence mechanisms are altered - allowing the bacterium to survive, multiply and go on to cause disease. The interaction between the APC and mycobacteria triggers a series of events, known as signalling cascades, resulting in the expression of molecules that determine whether APC will initiate a protective response or allow the progression towards disease. This proposal aims to study one of the major APC, called the alveolar macrophage. Residing in the lung, this cell is one of the first APC to come into contact with bacteria invading the body through the respiratory route. We will study how this bovine cell interacts with the TB-causing cattle strain M.bovis (which also causes TB in humans), BCG (vaccine strain) and M.tuberculosis (which causes disease in humans but not cattle). By comparing the response of the cell to the three different bacteria, we aim to identify alveolar macrophage responses only seen with the TB causing cattle strain, M.bovis. This should allow us to identify stages in the immune response where a particular reaction is critical if the bacterium is then going to cause disease rather than immunity, as seen with BCG and M.tuberculosis in cattle. This proposal aims to test the hypothesis that M.bovis ensures its survival within bovine alveolar macrophages and, as a consequence the progression of disease, by specific pattern recognition receptor usage and interference with the signalling cascades - influencing the outcome of the immune response. This contrasts with the receptors used and signalling cascades activated by BCG or M.tuberculosis, leading to the secretion of specific molecules by the infected cells that result in immunity rather than active disease. We propose that the difference in host specificity of M.bovis (includes cattle and humans) and M.tuberculosis (host specificity - only humans) and the virulence (ability to cause disease) of M.bovis (causes TB) and BCG (no disease, can develop immunity) in the bovine alveolar macrophage are key to the response of the cell and subsequent bacterial killing, and consequently critical to the outcome of exposure to the mycobacteria. A better understanding of the mechanisms in bovine alveolar macrophages that lead either to protective immunity or allow disease to develop is important for the development of novel therapies and vaccines.