The role of Tregs and lipid mediators in the progression of Mycobacterium leprae infection to active disease

麻风分枝杆菌是麻风的病原体，是一种高度传染性的专性细胞内细菌。绝大多数接触麻风分枝杆菌的人会感染麻风分枝杆菌，但只有一小部分受感染的人会发展为活动性疾病。先前对麻风病和结核病的研究表明，干扰素-γ（一种由病原体特异性记忆CD4 T细胞产生的效应细胞因子）在控制这些细胞内病原体感染方面发挥了重要作用。我们的初步数据显示，个体中麻风支原体特异性IFNγ水平逐渐降低，这与麻风支原体暴露水平和麻风患者细菌负荷指标相关。当我们评估麻风分枝杆菌与雪旺细胞和单核吞噬细胞的相互作用时，我们观察到抗炎细胞因子IL-10和脂质介质PGE-2的诱导作用。对麻风病患者病变和血清的代谢组学分析也表明，与麻风病临床形式和细菌负荷相关的多不饱和脂肪酸（PUFA）衍生脂质介质的存在存在明显差异。其他研究人员在麻风病患者的血液和病变中检测到Foxp-3阳性T细胞的频率，这与预期的多菌型麻风病中对麻风分枝杆菌的细胞免疫和效应功能的抑制有关。考虑到这些发现，我们假设麻风分枝杆菌与雪旺细胞和单核吞噬细胞的相互作用通过脂质介质的活性产生微环境，促进Treg抑制病原体特异性IFN-γ反应。我们将在以下具体目的的实验中验证这些假设：1 .评估麻风分枝杆菌感染者和麻风患者血液和皮肤病变中存在的Treg的表型和功能，确定Treg在麻风疾病期间Th1调节中的作用。研究麻风分枝杆菌感染个体炎症和免疫反应的特异性脂质介质及其对免疫反应的改变。免疫应答的负调控涉及几种不同的机制，这些机制存在于慢性感染、自身免疫性疾病和癌症的沉默、长期发展步骤的初始阶段，但在无症状个体中不太明显。利用流行病学和功能数据作为线索，观察活动性疾病发病前调节性T反应的变化，有可能降低与这些主要健康问题相关的个人和经济成本。

Mycobacterium leprae, the causative agent of leprosy, is a highly infectious obligate intracellular bacterium. The vast majority of the individuals exposed to M. leprae becomes infected, but only a small proportion of the infected individuals evolves to active disease. Previous work in leprosy and tuberculosis demonstrated a major role of interferon-γ, an effector cytokine produced by pathogen-specific memory CD4 T cells, in the control of the infection by these intracellular pathogens. Our preliminary data show a progressive reduction in M. leprae-specific IFNγ levels in individuals that correlates to indicators of level of exposure to M. leprae and to bacillary load in individuals with leprosy. When we evaluated the interaction of M. leprae with Schwann cells and mononuclear phagocytes, we observed an induction of the anti-inflammatory cytokine IL-10 and the lipid mediator PGE-2. Metabolomics analyses of lesions and sera from leprosy patients also demonstrated clear differences in the presence of polyunsaturated fatty acid (PUFA) derived lipid mediators that correlated to the clinical forms of leprosy and bacillary loads. Other investigators detected frequencies of Foxp-3 positive T cells in the blood and lesions of leprosy patients that correlate to the expected inhibition of cellular immunity and effector function against M. leprae in the multibacillary forms of leprosy. Taking in to account these findings, we hypothesize that M. leprae interactions with Schwann cells and mononuclear phagocytes generate a microenvironment via the activities of lipid mediator that facilitates the inhibition of pathogen-specific IFN-γ response by Treg. We will test these hypotheses in the experiments of the following specific aims: 1-Evaluate the phenotype and functionally the Treg present in the blood and skin lesions of M. leprae-infected individuals and leprosy patients, to define the role of Treg in Th1 regulation during leprosy disease. 2- Investigate specific lipid mediators of inflammatory and immune responses and their alteration of the immune responses in M. leprae- infected individuals. Negative regulation of the immune response entails several different mechanisms that are present but less visible in asymptomatic individuals in the initial stages of the silent, long-evolving steps of chronic infections, autoimmune diseases, and cancer. Looking at changes in regulatory T responses that precede the onset of active disease using epidemiological and functional data as clues has the potential for reducing the individual and economic costs associated to these major health problems.