Mentoring in Immunometabolic Dysregulation in TB and TB/HIV

结核病和结核病/艾滋病毒免疫代谢失调的指导

• 批准号: 9975724
• 负责人: Petros C Karakousis
• 金额: $ 19.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975724
• 关键词: 5' -AMP-activated protein kinase; Address; Animal Model; Antibiotics; Antimycobacterial Agents; Archives; Area; Attention; Automobile Driving; Bacteria; Bioinformatics; Biological Assay; Biological Markers; Cause of Death; Chronic; Clinical; Clinical Data; Complex; Development; Diagnosis; Diagnostic; Discipline; Disease; Drug resistance; Environment; Experimental Models; FRAP1 gene; Foam Cells; Fostering; Goals; HIV; HIV Seronegativity; HIV Seropositivity; HIV/TB; Homeostasis; Household; Human; Immune; Immune response; Immune system; Immunocompetent; Individual; Infection; International; Knowledge; Lesion; Lipid-Laden Macrophage; Lipids; Lung diseases; Machine Learning; Medical; Mentors; Metabolic; Metabolism; MicroRNAs; Mycobacterium tuberculosis; Necrosis; Outcome; Participant; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physicians; Population; Prevention; Preventive therapy; Proto-Oncogene Proteins c-akt; Pulmonary Tuberculosis; Regimen; Reporting; Research; Resources; Risk; Sampling; Scientific Advances and Accomplishments; Scientist; Serum; Signs and Symptoms; Sirtuins; South African; Specimen; Systems Biology; Techniques; Testing; Tissues; Training; Triglycerides; Tuberculosis; Validation; Whole Blood; Work; World Health Organization; antimicrobial; biobank; biosignature; career; chronic inflammatory disease; clinically relevant; cohort; cytokine; high risk; immunoregulation; improved; indexing; lifetime risk; lung injury; macrophage; monocyte; mycobacterial; novel; pathogen; patient oriented research; peripheral blood; prevent; programs; prospective; tool; transcriptome; transcriptome sequencing; tuberculosis granuloma; tuberculosis treatment

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.

结核病（TB）是全球艾滋病毒（PLWH）患者中死亡的主要原因。尽管 最近的科学进步，我们对免疫机制的理解仍然存在很大的差距 负责控制和根除结核分枝杆菌（MTB）感染。带潜在结核的PLWH 感染（LTBI）的年度患病风险约为10％，但是目前可用的测试 LTBI诊断降低了该人群的敏感性，无法预测哪些受到潜在感染 个人有针对性预防疗法的结核病风险最高。来自新兴数据 临床相关的动物模型表明LTBI和活性结核病代表了一系列免疫光谱 反应和宿主病理学，随着代谢变化和免疫失调的增加 过渡到结核病疾病。我们已经确定了独特的血清代谢产物和microRNA（miRNA）特征 能够区分结核病患者和非TB肺疾病患者。但是，这些 新颖的结核病签名尚未被前瞻性评估，以识别PLWH和HIV阴性的人 LTBI的TB进展风险增加。为了解决这一重要的知识差距 当前研究计划的1，学员将利用印度和南非报告纵向 结核病指数案例的家庭接触的生物库，以检验结核病是慢性的假设 与免疫调节和新陈代谢发生严重变化有关的炎性疾病 临床体征和症状的发作。全球结核病努力的另一个主要障碍是漫长的 以及复杂的电流抗结核方案，这与医学不坚持和 耐药性的出现。最近，注意力集中在宿主定向的辅助疗法上 优化对病原体的免疫反应并改善肺损伤。充满脂质的巨噬细胞 （泡沫细胞）通过提供有利的利基市场来维持慢性结核病感染至关重要 抗菌功能被下调，并通过诱导静脉曲张和组织损伤。最近的工作有 表明TB肉芽肿的富含泡沫细胞和坏死区域在甘油三酸酯中特别富集。 MTB 感染与甘油三酸酯稳态涉及的两种细胞途径的失调有关：A 涉及蛋白激酶B和MTOR复合物1（AKT/MTORC1）的促脂途径，以及抗 涉及AMP激活蛋白激酶和SIRTUINS（AMPK/SIRT）的脂肪生成途径。在AIM 2中，学员 将使用报告研究参与者的纵向临床样本和实验感染，从而 特征：（i）这些途径激活与控制临床MTB感染之间的关系， 以及抗脂肪性处​​理对感染人类巨噬细胞抗菌病功能的影响 前体。该研究的目标将与培养者的指导策略融合在一起 发展高影响患者的研究，并具有独立途径。