Host-Directed Therapy to Augment anti-M. tuberculosis Responses in the Setting of HIV Co-infection and to Sterilize the Tuberculoma

增强抗支原体的宿主定向治疗。

• 批准号: 10610310
• 负责人: Smriti Mehra
• 金额: $ 113.09万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610310
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Animals; Antibodies; Antigen-Antibody Complex; Antitubercular Agents; Apoptosis; BCG Live; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Coculture Techniques; Control Groups; Data; Development; Disease; Disease remission; Dose; Drug resistance; Epidemic; Event; Exhibits; Failure; Granuloma; Granulomatous; HIV; HIV Infections; HIV/TB; Health; Homing; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppressive Agents; Infection; Infection Control; Inflammatory; Inhalation; Interferon Type II; Knowledge; Lead; Lesion; Link; Lung; Lymphoid Tissue; Macaca; Macrophage; Measures; Mediating; Metabolic; Modeling; Morphology; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Myeloid Cells; Opportunistic Infections; Outcome; Pathogenesis; Pathology; Pathway interactions; Performance; Physiology; Population; Probability; Productivity; Pulmonary Tuberculosis; Recrudescences; Repression; Route; SIV; Sampling; Secondary to; Shapes; Signal Transduction; Site; Sterilization; Stress; Structure of parenchyma of lung; System; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; TNF gene; Testing; Tuberculoma; Tuberculosis; Tuberculosis Vaccines; Viral; Viral Load result; Virulence; adaptive immunity; antitumor drug; co-infection; comorbidity; disorder control; effectiveness study; exhaustion; immune function; immunogenic; immunoregulation; improved; in vitro Model; in vivo; inhibitor; lung lesion; mutant; nonhuman primate; novel; novel vaccines; pandemic disease; pathogen; prevent; programs; pulmonary granuloma; response; stem; transmission process; tuberculosis chemotherapy; tuberculosis granuloma; tuberculosis treatment; vaccine development; viral transmission

Abstract  Mycobacterium tuberculosis (Mtb) infection can lead to tuberculosis (TB) disease, causing ~9 million new infections and ~1.8 million deaths globally, every year. A quarter of these are deaths due to the TB/AIDS comorbidity, caused by Mtb/HIV co-infection and the resulting reactivation of LTBI. 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 in order to persist in the lungs of its hosts. As part of its virulence cycle, Mtb modulates host immunity. We have developed a robust macaque model Mtb/HIV 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. Using our model, we show that the expression of IDO (INDO, IDO1), a powerful immunosuppressant of activated CD4+ T cells, is dramatically enhanced in the lung granulomata of macaques. Levels of IDO are induced in a bacterial burden specific manner in myeloid cells. Thus, macaques that control inhaled Mtb infection as LTBI, do not express high levels of IDO in lung lesions, but those that progress to ATB do. IDO levels decline when animals with ATB are chemotherapeutically treated. Upon co-infection with SIV, 2/3rds of the macaques with LTBI reactivate disease - only these animals exhibited lung IDO induction. Finally, nonpathogenic infection with avirulent mutants of Mtb failed to elicit the induction of IDO. Amelioration of IDO enzymatic activity by an FDA, approved, safe compound in-vivo resulted in significant reduction in clinical signs of TB, pathology and bacterial burden, and increased survival. This was accompanied by increased lung T cell proliferation and induction of bronchus associated lymphoid tissue (iBALT). These events reshaped the granuloma is two different ways: i) functionally granulomas from treated (IDO blockaded) animals exhibited no signatures of T cell exhaustion but instead higher expression of T cell differentiation, apoptosis, bacterial killing and lung tissue remodeling pathways; ii) morphologically, greater relocation of T cells was observed to the center of the granulomata. The profoundly better killing of Mtb in macrophages by CD4+ T cells could be modeled in-vitro, in a novel macaque macrophage:CD4+ T cell co- culture system. Our results strongly suggest that IDO modulates a complex immune/metabolic signaling network that promotes bacterial survival, immune dysfunction and disease. Thus, inhibition of IDO is a prime target for adjunctive HDT against the multidrug resistant TB epidemic. Based on these data, we postulate that IDO1-signaling is key to modulating immune responses in human-like lung granulomas. We now propose to leverage the macaque model of LTBI to study if IDO-blockade in-vivo can enhance granuloma performance and sterilize Mtb infection. SIV co-infection will be used to test this. Finally, we will treat Mtb/SIV co-infected animals with a gut homing T cell blocking a4b7 antibody in addition to blockading IDO. We postulate that this dual treatment will reduce the viral load thus preventing reactivation, and enhance the sterilizing potential of IDO blockade.

摘要 结核分枝杆菌（Mtb）感染可导致结核病（TB），造成约900万新 感染和约180万人死亡。其中四分之一是死于结核病/艾滋病 合并症，由Mtb/HIV合并感染和由此导致的LTBI再激活引起。结核病在非洲的死灰复燃 在过去的二十年里，结核病的流行可归因于抗结核疫苗卡介苗（BCG）的失败。 包括成人肺结核、抗药性的出现和艾滋病的流行。失败 控制结核病源于缺乏对毒力和致病机制的全面了解 被这种高度专业化和成功的病原体利用，以便在其宿主的肺部持续存在。的一部分 Mtb通过其毒力循环调节宿主免疫。 我们利用自然感染途径建立了一个稳定的猕猴Mtb/HIV共感染模型 以及使用猿猴免疫缺陷病毒（SIV）作为HIV的替代品。这种模式可以用来 在真实的体内环境中研究结核分枝杆菌的生理学。使用我们的模型，我们表明，表达的IDO (INDO IDO 1），一种激活的CD 4 + T细胞的强效免疫抑制剂，在肺中显著增强 猕猴的肉芽肿。在骨髓细胞中以细菌负荷特异性方式诱导IDO水平。 因此，将吸入性Mtb感染控制为LTBI的猕猴在肺损伤中不表达高水平的IDO， 但那些进展到ATB的人会。当ATB动物接受化疗时，IDO水平下降 治疗。在与SIV共感染后，2/3的LTBI猕猴重新激活疾病-只有这些动物 显示肺IDO诱导。最后，非致病性感染Mtb的无毒突变体未能引起 诱导IDO。通过FDA批准的安全化合物在体内改善IDO酶活性， 显著减少结核病的临床体征、病理学和细菌负荷，并增加存活率。这是 伴有肺T细胞增殖增加和支气管相关淋巴组织诱导 （iBALT）.这些事件重塑肉芽肿是两种不同的方式：i）功能性肉芽肿从治疗 (IDO阻断）动物没有表现出T细胞耗竭的特征，而是表现出T细胞的更高表达。 分化、凋亡、细菌杀伤和肺组织重塑途径; ii）在形态学上， 观察到T细胞重新定位到肉芽肿的中心。更好地杀死结核分枝杆菌， 巨噬细胞的CD 4 + T细胞可以在体外建模，在一种新的猕猴巨噬细胞：CD 4 + T细胞共 培养体系我们的研究结果强烈表明IDO调节复杂的免疫/代谢信号传导 促进细菌存活、免疫功能障碍和疾病的网络。因此，IDO的抑制是一个主要因素。 针对耐多药结核病流行的连续性HDT的目标。 基于这些数据，我们假设IDO 1信号传导是调节类人免疫应答的关键。 肺肉芽肿我们现在建议利用LTBI的猕猴模型来研究IDO阻断是否在体内 可以增强肉芽肿表现并消灭结核杆菌感染。SIV合并感染将用于测试这一点。 最后，我们将用肠归巢T细胞阻断a4 b7抗体治疗Mtb/SIV共感染的动物，此外， 封锁IDO我们假设这种双重治疗将降低病毒载量，从而防止再活化， 并增强IDO阻断的杀菌潜力。