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

“结核分枝杆菌感染期间 IDO 在色氨酸途径中的作用 –

• 批准号: 9387020
• 负责人: Smriti Mehra
• 金额: $ 20.26万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387020
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Animals; Antitubercular Agents; Ants; Autologous; BCG Vaccine; Bacillus (bacterium); C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cessation of life; Coculture Techniques; Cultured Cells; Data; Development; Dioxygenases; Disease; Drug resistance; Enzymes; Essential Amino Acids; Experimental Models; Failure; Granuloma; HIV; Host Defense; Human; Immune response; Immune system; Immunity; Immunologics; Immunology; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Interferons; Intervention; Knock-out; Kynurenine; Lead; Lesion; Life; Life Cycle Stages; Liquid substance; Literature; Lung; Lymphocyte; Macaca; Macaca mulatta; Mediating; Microbe; Modeling; Molecular; Mus; Mutation; Mycobacterium tuberculosis; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Play; Pleural; Process; Protein Isoforms; Pulmonary Tuberculosis; Recruitment Activity; Resistance; Rodent Model; Role; Route; SIV; Sampling; Signal Transduction; Stress; Suppressor-Effector T-Lymphocytes; System; T cell response; T-Lymphocyte; Tryptophan; Tuberculosis; Tuberculosis Vaccines; Virulence; Work; adaptive immune response; antimicrobial; base; chemotherapy; co-infection; congenic; experimental study; extracellular; heme a; immunoregulation; immunosuppressed; in vivo; indoleamine; inhibitor/antagonist; killings; macrophage; mycobacterial; outcome forecast; pandemic disease; pathogen; prevent; programs; pulmonary granuloma; response; stem; tuberculosis granuloma; vaccination against tuberculosis

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.

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 万人新感染和约 150 万人死亡。 过去二十年结核病的死灰复燃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、耐药性的出现和艾滋病的流行。结核病控制失败源于对这种高度专业化且成功的病原体在宿主肺部持续存在的毒力和发病机制缺乏完整的了解。大量数据表明，作为其毒力循环的一部分，结核分枝杆菌调节宿主免疫力。 然而，这些过程的真正范围可能尚未被发现。 这一失败与常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真实体内压力，无法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。 我们通过使用结核分枝杆菌感染的自然途径并使用猿猴免疫缺陷病毒（SIV）作为艾滋病毒的替代品，开发了结核病和结核病/艾滋病合并感染的稳健猕猴模型。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 HIV 合并感染引起的重新激活以及 BCG 疫苗接种保护的相关性。我们的初步数据表明，在两种忠实的人类结核病灶模型（即恒河猴和克拉斯尼克小鼠）的肺部经典肉芽肿病灶中，INDO (IDO1) 的表达显着增强。 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 是激活的 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，那里存在 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界限使得 Mtb 在宿主肺部持续存在和存活。 IDO1 表达的这种特殊内环分布表明，活跃的 Mtb 感染对受感染的巨噬细胞和旁观者巨噬细胞进行编程，以防止激活的 CD4+ 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本来研究 IDO1 在免疫抑制 Th1 对 Mtb 感染的反应以及病原体持续存在中的作用。 揭示这种潜在的潜伏机制可能为开发辅助结核病化疗的宿主定向免疫疗法铺平道路。