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

描述（由申请人提供）：结核病是一种影响全球健康的疾病。控制这种疾病需要大量资源，世界上资源贫乏地区的发病率和死亡率最高。尽管有专门的研究努力，宿主免疫系统在结核分枝杆菌感染中的几个方面的作用仍然超出了我们的理解。我们认为，更好地了解结核病过程中的免疫将有助于确定发展为结核病或发展为更严重疾病的风险增加的个人或人群，以及结核病治疗的新目标。为此，我们希望将注意力集中在宿主免疫在结核病感染中的作用，特别是先天介质巨噬细胞迁移抑制因子（MIF）的作用。已知MIF参与多种风湿病和传染病的发病机制。虽然它被认为有助于类风湿关节炎、血管炎和休克动物模型的有害炎症，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。为了这项应用，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，并对结核病患者群体中功能显著的MIF多态性进行初步调查。利用分枝杆菌感染缺乏MIF的巨噬细胞，我们将探讨MIF在识别病原体、产生炎症介质（细胞因子、一氧化氮、活性氧）和巨噬细胞功能（激活诱导的凋亡和吞噬）中的作用。接下来，我们将研究野生型和MIF缺陷小鼠的结核感染，以确定MIF在存活、分枝杆菌控制和病理中的作用。此外，MIF基因的人类多态性已经被确定，这在人群中产生了MIF的高生产者和低生产者。MIF的低生产者对某些传染性病原体的易感性增加，而对其他传染性病原体的易感性相对较低。在研究的最后阶段，我们将在肺结核患者和匹配对照人群中使用MIF基因分型技术，以确定在肺结核感染患者中是否更频繁地发现MIF低生产者。基于我们在这项关于MIF在结核病发病机制中的作用的第一项研究中获得的结果，我们计划对MIF基因型和从结核病感染发展为疾病的风险进行更大规模的人群调查，并开始评估MIF在结核病感染的先天免疫应答中的作用的治疗意义。

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.