Role of Macrophage Migration Inhibitory Factor (MIF) in the Pathogenesis of Tuber

描述(申请人提供)：结核病是一种影响全球健康的疾病。控制这一疾病需要大量资源，在世界上资源匮乏的地区，发病率和死亡率成本最高。尽管致力于研究，但宿主免疫系统在结核分枝杆菌感染中的作用的几个方面仍然超出了我们的理解。我们认为，更好地了解结核病病程中的免疫力将有助于识别罹患结核病或发展为更严重疾病的风险更高的个人或人群，以及结核病治疗的新目标。为此，我们想重点关注宿主免疫在结核病感染中的作用，特别是天然介质巨噬细胞移动抑制因子(MIF)的作用。已知MIF参与了多种风湿病和传染病的发病机制。虽然在类风湿性关节炎、血管炎和休克动物模型中，它被认为是有害的炎症，但它对控制细胞内病原体(沙门氏菌、弓形虫和利什曼原虫)的感染至关重要。在这个应用中，我们将研究MIF在结核病发病机制中的作用，特别关注先天免疫，在小鼠模型中建立表型，并在结核病患者群体中进行功能显著的MIF多态的初步调查。利用MIF缺乏的巨噬细胞的分枝杆菌感染，我们将讨论MIF在识别病原体、产生炎症介质(细胞因子、一氧化氮、活性氧物种)和巨噬细胞功能(激活诱导的凋亡和吞噬)中所起的作用。接下来，我们将追踪野生型和MIF缺陷小鼠的结核感染，以确定MIF在生存、分枝杆菌控制和病理中的作用。此外，人类MIF基因的多态已经被发现，这在人群中产生了MIF的高产生者和低产生者。MIF的低产量增加了对某些感染性病原体的易感性，而他们对其他病原体的保护相对较好。在我们研究的最后阶段，我们将利用MIF基因分型技术，在肺结核患者和匹配的对照组中，确定是否在结核病感染患者中发现低产生MIF的频率更高。基于我们在第一个关于MIF在结核病发病机制中的作用的研究中获得的结果，我们计划对MIF基因和从结核病感染进展到疾病的风险进行更大范围的人群调查，并开始评估MIF在结核病感染的先天免疫反应中的作用的治疗意义。 公共卫生相关性：结核病是一种对全球健康有影响的疾病。该项目旨在更好地了解引起结核病的细菌与受感染宿主的免疫系统之间的相互作用。这项研究的目标是帮助确定影响结核病易感性的因素，并确定提高免疫力的方法，将其作为抗击结核病的战略。

DESCRIPTION (provided by applicant): Tuberculosis is a disease with global health implications. Control of the disease utilizes a large amount of resources, with the greatest morbidity and mortality costs in resource-poor areas of the world. Despite dedicated research efforts, several aspects of the role of the host immune system in Mycobacterium tuberculosis infection remain beyond our understanding. We maintain that a better understanding of immunity in the course of tuberculosis disease will lead to identification of individuals or populations at increased risk of progressing to tuberculosis disease or developing more severe illness, as well as new targets for tuberculosis treatment. To this end, we would like to focus our attention on host immunity in tuberculosis infection, particularly, the role of the innate mediator, macrophage migration inhibitory factor (MIF). MIF is known to participate in the pathogenesis of a variety of rheumatologic and infectious diseases. While it is thought to contribute to detrimental inflammation in rheumatoid arthritis, vasculitis, and animal models of shock, it is crucial to control of infection with intracellular pathogens (Salmonella, Toxoplasma, and Leishmania). For this application, we will investigate the role of MIF in tuberculosis pathogenesis with special attention to innate immunity, establish the phenotype in a murine model, and perform a preliminary investigation of functionally significant MIF polymorphisms in a population of patients with tuberculosis. Using mycobacterial infection of MIF-deficient macrophages we will address the role that MIF plays in recognition of the pathogen, production of inflammatory mediators (cytokines, nitric oxide, reactive oxygen species), and macrophage function (activation-induced apoptosis and phagocytosis). We next will pursue tuberculosis infection in wild type and MIF-deficient mice to ascertain the role of MIF in survival, mycobacterial control, and pathology. Additionally, human polymorphisms in the MIF gene have been identified, which create high-producers and low-producers of MIF in population. Low-producers of MIF have increased susceptibility to some infectious pathogens, whereas they are relatively protected from others. For the final stage of our investigation, we will utilize MIF genotyping techniques in a population of patients with pulmonary tuberculosis and matched controls, to determine whether low-producers of MIF are identified more frequently among tuberculosis infected patients. Based upon results we obtain in this first study of the effect of MIF in the pathogenesis of tuberculosis, we plan to pursue larger population investigations of MIF genotype and the risk of progressing from tuberculosis infection to disease, and begin to assess the therapeutic implications for MIF's role in innate immune responses to tuberculosis infection. PUBLIC HEALTH RELEVANCE: Tuberculosis is a disease with global health implications. This project aims to better understand the interactions between the bacterium that causes tuberculosis and the immune system of the infected host. The goal of this research is to help determine factors that affect susceptibility to tuberculosis, and identify ways to boost immunity as a strategy in combating the disease.