The role of platelets in the innate inflammatory response to TB.

结核病（TB）每年导致150多万人死亡，并且对用于治疗该疾病的抗生素的耐药性不断增加。新的抗结核药物很少，需要新的治疗方法。在结核病中，免疫系统过度活跃，炎症损害肺组织。这是一个复杂的过程，涉及我们自己的一系列免疫细胞。更好地了解这一过程应该有助于确定开发新疗法的机会，以减少炎症和组织损伤。有证据表明，血小板，血液中通常与血液凝固有关的细胞，在调节免疫系统方面也很重要。他们已被证明是重要的，在许多不同的疾病，涉及炎症，包括癌症和关节炎，但很少有人知道他们的作用和他们在结核病的重要性。该项目的背景工作表明，血小板增加炎症标志物的水平，这些标志物是由免疫系统的细胞感染结核病时产生的。我还发现，与健康对照组相比，结核病患者血液中血小板衍生因子的浓度更高，当患者接受结核病治疗时，这些水平下降。这些结果支持了我的研究背后的主要思想，即血小板在调节人类免疫系统对结核病的反应中很重要。我的项目有两个部分：1.我将研究血小板对单核细胞产生炎症标志物的影响，单核细胞是人体免疫系统的细胞。使用我在以前的工作中使用的技术，我将从健康供体的血液中获得单核细胞和血小板。我将测量结核病感染后单核细胞产生的炎症标志物，以及使用称为qPCR的技术测量这些细胞的基因表达。我将研究血小板如何影响免疫细胞，包括研究血小板和免疫细胞之间直接接触的重要性，作为调节炎症和结核菌生长的一种方式。2.然后，我将重点介绍结核病患者在抗结核治疗前、治疗中和治疗后血小板活化的临床重要性。我将检查上述工作提出的目标，以确认它们的效果可以在实验室实验中在患者和细胞中得到证实。我将招募120名成年结核病患者（仅药物敏感性疾病）和相同数量的年龄和性别匹配的健康对照。所有受试者均为HIV阴性。我将收集有关患者的临床和X光数据以及结核病感染留下的任何疤痕。患者将进行一项称为肺量测定的测试来测量肺功能。这将在结核病患者治疗结束时进行，并在健康对照组中进行比较。在治疗前、14天和56天后以及治疗结束时，将从患者中采集30 ml血液。血液将用于测量血小板活化，部分血液将在-70 ℃下冷冻，用于随后的血小板因子测量，其余血液用于获得血小板和白色血细胞计数。一些患者将有一个程序称为支气管镜检查作为他们的临床护理的一部分。将从这些患者中获得肺部液体，并检测细胞和液体是否存在血小板活性的证据。总之，这些结果将使我了解结核病患者的血小板和免疫反应发生了什么。总之，该项目将产生有关血小板在结核病中作用的数据。这是一个令人兴奋的新领域，可能会影响未来的结核病治疗。它还将为我提供一个优秀的临床和实验室科学培训，我需要作为一个临床学术进步。

Tuberculosis (TB) causes over 1.5 million deaths each year and there is increasing resistance to antibiotics used to treat the disease. There are few new anti-TB drugs, and new approaches to treating patients are required. In TB the immune system is overactive, and inflammation damages the lung tissues. This is a complex process involving a range of our own immune cells. Understanding this process better should help to identify opportunities to develop new treatments that reduce inflammation and tissue damage. There is evidence that platelets, cells in the blood that are usually associated with blood clotting, are also important in regulating the immune system. They have been shown to be important in many different diseases that involve inflammation including cancer and arthritis, but very little is known about their role and their importance in TB.Background work for this project shows that platelets increase levels of markers of inflammation that are produced by cells of the immune system when they are infected with TB. I also found that patients with TB have higher concentrations of platelet-derived factors in their blood compared to healthy controls, and these levels decreased when the patients were given TB treatment. The main idea behind my research, which is that platelets are important in regulating the human immune system's response to tuberculosis, is supported by these results.My project has 2 parts:1. I shall study the effect of platelets on production of markers of inflammation by monocytes, which are cells of the human immune system. Using techniques I have used in my previous work, I will obtain monocytes and platelets from blood taken from healthy donors. I will measure inflammatory markers produced by monocytes with and without platelets following TB infection, as well as measuring gene expression from these cells using a technique called qPCR. I will look at how platelets may affect the immune cells including studying the importance of direct contact between the platelets and the immune cells as a way of regulating inflammation and TB bacterial growth. 2. I shall then focus on the clinical importance of platelet activation in patients with TB before, during, and after anti-TB treatment. I will examine targets suggested by the work above to confirm that their effects can be demonstrated in patients as well as in cells in laboratory experiments. I shall recruit 120 adult TB patients (drug-sensitive disease only) and the same number of age- and sex-matched healthy controls. All subjects will be HIV-negative. I will collect clinical and X-ray data about the patients and any scarring left by infection with tuberculosis. Patients will have a test called spirometry to measure lung function. This will be done for TB patients at the end of their treatment, and in healthy controls for comparison. 30mls blood will be taken from patients before treatment, after 14 and 56 days, and at the end of treatment. The blood will be used to measure platelet activation and some will be frozen at -70C for later measurement of platelet factors, and the remainder used to obtain platelet and white blood cell counts. Some patients will have a procedure called a bronchoscopy as part of their clinical care. Fluid from the lungs will be obtained from these patients, and the cells and fluid tested for evidence of platelet activity. Together, these results will allow me to understand what is happening in terms of platelets and the immune response in TB patients. In summary, this project will produce data about the role of platelets in TB. This is a new and exciting area that might affect TB treatment in the future. It will also provide me with an excellent clinical and laboratory science training that I need to progress as a clinical academic.