Mentoring in Immunometabolic Dysregulation in TB and TB/HIV

结核病（TB）是全世界艾滋病毒感染者（PLWH）死亡的主要原因。尽管 尽管最近的科学进步，我们对免疫机制的理解仍然存在重大差距 负责控制和根除结核分枝杆菌（Mtb）感染。潜伏性结核病感染者 感染（LTBI）进展为TB疾病的年风险约为10%，然而目前可用的检测方法 LTBI诊断在该人群中的敏感性降低，并且不能预测哪些潜伏感染 个体发展为结核病的风险最高，需要有针对性的预防性治疗。新兴数据来自 临床相关的动物模型表明，LTBI和活动性TB代表了一种免疫反应谱， 反应和宿主病理学，随着代谢变化和免疫失调的增加， 向结核病过渡。我们已经确定了独特的血清代谢物和microRNA（miRNA）谱， 能够区分肺结核患者和非肺结核患者。但这些 尚未对新的结核病特征进行前瞻性评估，以确定PLWH和HIV阴性者， LTBI患者的TB进展风险增加。为了弥补这一巨大的知识差距， 1目前的研究计划，学员将利用印度和南非的报告纵向 结核病指标病例家庭接触者的生物储存库，以检验结核病是一种慢性疾病的假设 与免疫调节和代谢的深刻变化相关的炎性疾病， 出现临床体征和症状。全球结核病根除工作的另一个主要障碍是漫长的 和复杂的当前抗结核治疗方案，这是与医疗不遵守和 耐药性的出现。最近，注意力集中在宿主导向的抗肿瘤治疗上， 优化对病原体的免疫反应和改善肺损伤。载脂巨噬细胞 (foam细胞）是维持慢性结核病感染的核心，提供了一个有利的生态位， 抗微生物功能下调，并通过诱导干酪化和组织损伤。最近的工作已经 显示泡沫细胞丰富和TB肉芽肿的坏死区域特别富含甘油三酯。MTB 感染与参与甘油三酯稳态的两种细胞途径的失调有关： 涉及蛋白激酶B和mTOR复合物1（Akt/mTORC 1）的促脂肪生成途径，以及抗- 脂肪生成途径涉及AMP活化蛋白激酶和sirtuins（AMPK/SIRT）。在目标2中， 将使用来自RePORT研究参与者的纵向临床样本和离体实验感染， 表征：（i）这些途径的活化与临床Mtb感染的控制之间的关系， 以及抗脂肪生成治疗对感染人巨噬细胞的抗分枝杆菌功能的影响 离体。研究目标将与指导战略相结合，为学员培养 发展高影响力的以患者为导向的研究，并提供独立的途径。

Tuberculosis (TB) is the leading cause of death among people living with HIV (PLWH) worldwide. Despite recent scientific advances, significant gaps remain in our understanding of the immune mechanisms responsible for control and eradication of Mycobacterium tuberculosis (Mtb) infection. PLWH with latent TB infection (LTBI) have a ~10% annual risk of progressing to TB disease, however currently available tests for LTBI diagnosis have reduced sensitivity in this population and are not able to predict which latently infected individuals are at highest risk for developing TB for targeted preventive therapy. Emerging data from clinically relevant animal models suggest that LTBI and active TB represent a spectrum of immune responses and host pathology, with increasing metabolic changes and immune dysregulation during the transition to TB disease. We have identified unique serum metabolite and microRNA (miRNA) profiles that are able to discriminate between patients with TB and those with non-TB lung disease. However, these novel TB signatures have not been assessed prospectively to identify PLWH and HIV-negative persons with LTBI who are at increased risk for TB progression. In order to address this significant knowledge gap, in Aim 1 of the current research program, trainees will leverage the Indian and South African RePORT longitudinal biorepositories of household contacts of TB index cases to test the hypothesis that TB is a chronic inflammatory disease associated with profound changes in immune regulation and metabolism prior to the onset of clinical signs and symptoms. Another major barrier to global TB eradication efforts is the lengthy and complicated current anti-tubercular regimen, which is associated with medical nonadherence and the emergence of drug resistance. Recently, attention has focused on host-directed adjunctive therapies aimed at optimizing immune responses to the pathogen and improving lung damage. Lipid-laden macrophages (foam cells) are central to maintaining chronic TB infection by providing a favorable niche in which antimicrobial functions are down-regulated, and by inducing caseation and tissue damage. Recent work has shown that foam-cell-rich and necrotic areas of TB granulomas are particularly enriched in triglycerides. Mtb infection is associated with dysregulation of two cellular pathways involved in triglyceride homeostasis: a pro-lipogenic pathway involving protein kinase B and mTOR complex 1 (Akt/mTORC1), and an anti- lipogenic pathway involving AMP-activated protein kinase and the sirtuins (AMPK/SIRT). In Aim 2, trainees will use longitudinal clinical samples from RePORT study participants and experimental infections ex vivo to characterize: (i) the relationship between activation of these pathways and control of clinical Mtb infection, and the effect of anti-lipogenic treatments on antimycobacterial functions of human macrophages infected ex vivo. The research aims will be integrated with a mentoring strategy for mentees that fosters development of high impact patient-oriented research with a pathway to independence.