Mentoring in Immunometabolic Dysregulation in TB and TB/HIV

结核病(TB)是全世界艾滋病毒携带者(PLWH)的主要死亡原因。尽管 最近的科学进步，在我们对免疫机制的理解上仍然有很大的差距 负责控制和根除结核分枝杆菌(Mtb)感染。PLWH合并潜伏性结核病 感染(LTBI)每年有大约10%的风险进展为结核病，但目前可用的检测方法 LTBI诊断降低了这一人群的敏感度，无法预测哪些潜伏感染 个人患结核病的风险最高，需要进行有针对性的预防治疗。来自以下方面的新兴数据 临床相关的动物模型表明，LTBI和活动性结核病代表了一系列免疫 反应和宿主病理，随着代谢变化和免疫失调的增加 过渡到结核病。我们已经确定了独特的血清代谢物和微RNA(MiRNA)图谱 能够区分结核病患者和非结核病肺部疾病患者。然而，这些 尚未对新的结核病签名进行前瞻性评估，以识别PLWH和HIV阴性的患者 LTBI是结核病进展风险增加的人群。为了解决这一重大的知识差距，在AIM 在目前的研究计划中，受训者将利用印度和南非的纵向报告 结核病指示病例家庭接触者的生物库，以检验结核病是慢性病的假设 与免疫调节和代谢发生深刻变化相关的炎症性疾病 出现临床症状和体征。全球根除结核病努力的另一个主要障碍是漫长的 和复杂的当前抗结核方案，这与药物不坚持和 出现抗药性。最近，人们的注意力集中在针对宿主的辅助治疗上。 优化对病原体的免疫反应，改善肺损伤。富含脂质的巨噬细胞 (泡沫细胞)是维持慢性结核病感染的核心，因为它提供了一个有利的利基环境 抗菌功能被下调，并通过诱导干酪和组织损伤。最近的工作有 结果显示，结核肉芽肿的泡沫细胞丰富和坏死区特别富含甘油三酯。山地车 感染与参与甘油三酯稳态的两个细胞通路的失调有关：A 涉及蛋白激酶B和mTOR复合体1的促脂肪生成途径(Akt/mTORC1)，以及一种抗 涉及AMP激活的蛋白激酶和sirtuins的造脂途径(AMPK/SIRT)。在目标2中，受训人员 将使用来自报告研究参与者和体外实验感染的纵向临床样本 特征：(I)这些通路的激活与临床结核分枝杆菌感染控制之间的关系， 抗脂治疗对感染人巨噬细胞抗分枝杆菌功能的影响 体外实验。研究目标将与针对被辅导者的指导战略相结合，以促进 发展高影响力、以患者为导向的研究，为独立提供一条途径。

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.