"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）疾病，每年在全球造成约900万新感染和约150万人死亡。 在过去的二十年中，结核病的复兴可以归因于抗TB疫苗，巴基氏疫苗，巴奇氏菌（BCG）在含有成年的成年，肺结核中的失败，药物抗性和艾滋病的出现。无法控制结核病的原因是由于缺乏对这种高度专业化和成功的病原体所利用的毒力和发病机理程序，可以持续存在于其宿主的肺中。大量数据表明，作为其毒力周期的一部分，MTB调节宿主免疫力。 但是，这些过程的真正范围可能还没有被发现。 该故障与经常使用的结核病模型无法准确概括人类结核直接相关。体外和古典啮齿动物模型无法产生MTB在人类肺部遇到的体内应力的真实广度，作为其生命周期的一部分，未能模拟以paucibibacillagary感染或病理学和疾病的各种进展为特征的潜伏期。 我们通过使用MTB感染的自然路线并将邻苯二醇免疫缺陷病毒（SIV）作为HIV的替代物，开发了TB和TB/AIDS共感染的强大猕猴模型。可以利用该模型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BCG疫苗接种引起的保护的相关性。我们的初步数据表明，在两个忠实的人类TB病变模型的肺中存在的经典肉芽肿病变中，印度（IDO1）的表达显着增强，即恒河猴以及Krasnik小鼠。 此外，至少在NHP病变中，IDO1的表达仅限于富含巨噬细胞的内部，而不是病变的淋巴细胞富含淋巴细胞。 IDO1编码吲哚胺2,3，二氧酶，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，基于可用的数据和文献，我们假设IDO1负责使活化的CD4+ T细胞远离颗粒瘤的中心，其中MTB感染了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的特殊界限远离病变中心，使MTB能够在宿主肺中持续并存活。 IDO1表达的这种专门的内环分布表明，活跃的MTB感染程序感染了和旁观者巨噬细胞，以防止活化的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存储样本来研究IDO1在免疫抑制TH1对MTB感染的反应以及病原体持久性中的作用。 阐明这种潜在潜在的潜在机制可能为开发宿主的定向免疫疗法辅助地添加到抗抗TB化学疗法的道路上铺平了道路。