"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150万人死亡。结核病在过去二十年中的死灰复燃可归因于抗结核疫苗卡介苗（BCG）在控制成人结核病和肺结核方面的失败、耐药性的出现以及艾滋病的流行。结核病控制的失败源于缺乏对这种高度特化和成功的病原体在其宿主肺部持续存在所利用的毒力和发病机制的完全了解。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。然而，这些过程的真正范围可能尚未被揭示。这一失败与经常使用的结核病实验模型无法准确概括人类结核病有直接关系。体外和经典的啮齿动物模型无法产生结核分枝杆菌在人肺内作为其生命周期的一部分所遇到的体内应激的真实广度，无法模拟以少杆菌感染为特征的潜伏期，也无法模拟病理和疾病的各种进展。我们利用结核分枝杆菌感染的自然途径和猴免疫缺陷病毒（SIV）作为HIV的替代物，建立了一个健壮的结核和结核/艾滋病联合感染的猕猴模型。该模型可用于在真实的体内环境中研究结核分枝杆菌的生理学。此外，利用我们的模型可以研究HIV合并感染引起的再激活和卡介苗接种引起的保护的相关性。我们的初步数据表明，INDO （IDO1）的表达在两种可靠的人类结核病模型，即恒河猴和Krasnik小鼠的肺部经典肉芽肿病变中显着增强。此外，至少在NHP病变中，IDO1的表达仅限于病变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。IDO1编码吲哚胺2,3双加氧酶，一种色氨酸分解代谢酶。IDO1是激活CD4+ T细胞的强大免疫抑制剂。因此，根据现有的数据和文献，我们假设IDO1负责使活化的CD4+ T细胞远离肉芽肿中心，而肉芽肿中心是Mtb感染的巨噬细胞和细胞外Mtb存在的地方。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灶中心的特殊界限允许结核分枝杆菌在宿主肺部持续存在并存活。这种IDO1表达的特殊内环分布表明，活跃的Mtb感染程序感染和旁观者巨噬细胞阻止活化的CD4+ T细胞进入病原体感染的肉芽肿区域。我们将利用巨噬细胞培养模型和储存样本来研究IDO1在Mtb感染免疫抑制Th1反应和病原体持久性中的作用。揭示这种潜在的潜伏期机制可能为开发宿主定向免疫疗法辅助抗结核化疗铺平道路。

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.