"Role of IDO in tryptophan pathway during Mycobacterial tuberculosis infection”

结核分枝杆菌（Mtb）感染可导致结核病（TB），每年在全球造成约900万新感染和约150万死亡。 结核病在过去二十年中的重新抬头可归因于抗结核疫苗卡介苗（BCG）在控制成人肺结核方面的失败，以及抗药性的出现和艾滋病的流行。控制结核病的失败源于缺乏对这种高度专业化和成功的病原体在其宿主肺部持续存在的毒力和发病机制程序的完全理解。大量数据表明，作为其毒力周期的一部分，结核分枝杆菌调节宿主免疫力。 然而，这些进程的真正范围可能尚未被发现。 这一失败与经常使用的结核病实验模型无法准确再现人类结核病直接相关。体外和经典的啮齿动物模型不能产生Mtb在人肺内所遇到的作为其生命周期的一部分的体内应激的真实广度，不能模拟以少杆菌感染为特征的潜伏期，或各种病理和疾病进展。 我们已经开发了一个强大的结核病和结核病/艾滋病共感染的猕猴模型，通过使用结核分枝杆菌感染的自然途径，并通过使用猿猴免疫缺陷病毒（SIV）作为HIV的替代品。该模型可用于在真实的体内环境中研究Mtb的生理学。 此外，可以使用我们的模型研究由于HIV共感染以及由于BCG疫苗接种的保护而导致的再激活的相关性。我们的初步数据表明，INDO（IDO 1）的表达显着增强，在典型的肉芽肿病变存在于两个忠实的模型，即恒河猴以及克拉希尼克小鼠的肺结核病变。 此外，至少在NHP病变中，IDO 1的表达局限于病变的富含巨噬细胞的内部区域，而不是富含淋巴细胞的外部区域。IDO 1编码吲哚胺2，3双加氧酶，一种色氨酸分解代谢酶。IDO 1是活化的CD 4 + T细胞的强效免疫抑制剂。 因此，基于现有数据和文献，我们假设IDO 1负责保持活化的CD 4 + T细胞远离肉芽肿中心，其中存在Mtb感染的巨噬细胞以及细胞外Mtb。 这些T细胞可以消除感染，因此我们进一步假设，它们远离病变中心的特殊分界允许Mtb在宿主肺内持续存在并存活。IDO 1表达的这种特化内环分布表明，活性Mtb感染程序感染的和旁观者巨噬细胞，以防止活化的CD 4 + T细胞进入肉芽肿的病原体感染区域。 我们将利用巨噬细胞培养模型和库存样品来研究IDO 1在免疫抑制Th 1对Mtb感染的反应和病原体的持久性中的作用。 揭示这种潜在的潜伏机制可能为开发抗结核化疗的宿主定向免疫疗法铺平道路。

Mycobacterium tuberculosis (Mtb) infection can lead to tuberculosis (TB) disease, causing ~ 9 million new infections and ~ 1.5 million deaths globally, every year. The resurgence of TB in the last two decades can be attributed to the failure of the anti-TB vaccine, Bacille Calmette-Guerin (BCG) in containing adult, pulmonary TB as well, the emergence of drug-resistance and the AIDS pandemic. The failure to control TB stems from the lack of complete understanding of the virulence and pathogenesis programs utilized by this highly specialized and successful pathogen to persist in the lungs of its hosts. A large volume of data points to the fact that as part of its virulence cycle, Mtb modulates host immunity. However, the true scope of these processes may yet not have been uncovered. This failure is directly related to the inability of the often-used experimental models of TB to accurately recapitulate human TB. In-vitro and classical rodent models fail to generate the true breadth of in-vivo stresses encountered by Mtb within human lungs as part of its life cycle, fail to model latency characterized by paucibacillary infection, or various progression to pathology and disease. We have developed a robust macaque model of TB and TB/AIDS co-infection, by using natural routes of Mtb infection and by using Simian Immunodeficiency Virus (SIV) as a surrogate for HIV. This model can be leveraged to study the physiology of Mtb in a true in-vivo setting. Furthermore, correlates of reactivation due to HIV co-infection as well as protection due to BCG vaccination could be studied using our model. Our preliminary data indicates that the expression of INDO (IDO1) is dramatically enhanced in classical granuloma lesions present in the lungs of two faithful models of human TB lesions, namely the rhesus macaques as well as the Krasnik mice. Furthermore, at least in NHP lesions, the expression of IDO1 is confined to the macrophage rich inner and not the lymphocyte rich outer-region of the lesion. IDO1 encodes for indoleamine 2,3, dioxygenase, a tryptophan catabolic enzyme. IDO1 is a powerful immunosuppressant of activated CD4+ T cells. Thus, based on the available data and literature, we hypothesize that IDO1 is responsible for keeping activated CD4+ T cells away from the center of the granuloma, where Mtb infected macrophages as well as extracellular Mtb are present. These T cells can eliminate infection, and thus we further hypothesize that their special demarcation away from the lesion-center allows Mtb to persist and survive within host lungs. This specialized inner ring distribution of IDO1 expression indicates that active Mtb infection programs infected and bystander macrophages to prevent activated CD4+ T cells from accessing the pathogen infected regions of the granuloma. We will utilize macrophage culture model and banked samples to study the role of IDO1 in immunosuppressing Th1 responses to Mtb infection and in the persistence of the pathogen. Unraveling this potential mechanism of latency may pave the way for the development of host directed immunotherapies adjunctive to anted TB chemotherapy.