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: 10429990
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429990
• 关键词: 5' -AMP-activated protein kinase; Address; Animal Model; Antibiotics; Antimycobacterial Agents; Area; Attention; Automobile Driving; Bacteria; Bioinformatics; Biological Assay; Biological Markers; Cause of Death; Chronic; Clinical; Clinical Data; Complex; Development; Diagnosis; Discipline; Disease; Drug resistance; Environment; 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; Macrophage; Medical; Mentors; Metabolic; Metabolism; MicroRNAs; Modeling; Mycobacterium tuberculosis; Necrosis; Outcome; Participant; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physicians; Population; Predisposition; 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; diagnostic tool; high risk; immunoregulation; improved; indexing; lifetime risk; lung injury; monocyte; multiplex assay; novel; pathogen; patient oriented research; peripheral blood; prevent; programs; progression risk; prospective; risk prediction; sample archive; 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) 是全球艾滋病毒感染者 (PLWH) 死亡的主要原因。尽管 最近的科学进展，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) 每年进展为结核病的风险约为 10%，但目前可用的检测方法 LTBI 诊断降低了该人群的敏感性，并且无法预测哪些潜伏感染者 接受针对性预防治疗的个体患结核病的风险最高。新兴数据来自 临床相关动物模型表明 LTBI 和活动性结核病代表了一系列免疫 反应和宿主病理学，随着代谢变化和免疫失调的增加 转变为结核病。我们已经确定了独特的血清代谢物和 microRNA (miRNA) 谱， 能够区分结核病患者和非结核病肺病患者。然而，这些 尚未对新的结核病特征进行前瞻性评估，以识别感染者和艾滋病毒阴性者 结核病进展风险增加的 LTBI。为了解决这一重大知识差距，Aim 在当前研究计划的第 1 项中，学员将利用印度和南非纵向报告 结核病指数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 炎症性疾病与免疫调节和代谢的深刻变化相关 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长期的 目前的抗结核治疗方案复杂，这与医疗不依从性和 耐药性的出现。最近，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并改善肺部损伤。富含脂质的巨噬细胞 （泡沫细胞）通过提供有利的生态位，对于维持慢性结核感染至关重要 抗菌功能被下调，并引起干酪样变和组织损伤。最近的工作有 研究表明，结核肉芽肿的富含泡沫细胞和坏死区域的甘油三酯特别丰富。山地车 感染与参与甘油三酯稳态的两条细胞途径的失调有关： 促脂肪生成途径涉及蛋白激酶 B 和 mTOR 复合物 1 (Akt/mTORC1)，以及抗 脂肪生成途径涉及 AMP 激活蛋白激酶和去乙酰化酶 (AMPK/SIRT)。在目标 2 中，受训者 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）这些途径的激活与临床结核分枝杆菌感染的控制之间的关系， 以及抗脂肪生成治疗对感染的人巨噬细胞抗分枝杆菌功能的影响 离体。研究目标将与受训者的指导策略相结合，以促进 发展高影响力的以患者为导向的研究，并提供独立的途径。

项目成果

The Global Health Security Index is not predictive of coronavirus pandemic responses among Organization for Economic Cooperation and Development countries.

全球健康安全指数不能预测经济合作与发展组织国家之间的冠状病毒大流行反应。

• 发表时间: 2020
• 影响因子: 3.7
• 作者: Abbey, Enoch J;Khalifa, Banda A A;Oduwole, Modupe O;Ayeh, Samuel K;Nudotor, Richard D;Salia, Emmanuella L;Lasisi, Oluwatobi;Bennett, Seth;Yusuf, Hasiya E;Agwu, Allison L;Karakousis, Petros C
• 通讯作者: Karakousis, Petros C

Mechanisms of Antibiotic Tolerance in Mycobacterium avium Complex: Lessons From Related Mycobacteria.

鸟分枝杆菌复合体的抗生素耐受机制：相关分枝杆菌的经验教训。

• 发表时间: 2020
• 作者: Parker, Harley;Lorenc, Rachel;Ruelas Castillo, Jennie;Karakousis, Petros C
• 通讯作者: Karakousis, Petros C

Targeting the Mycobacterium tuberculosis Stringent Response as a Strategy for Shortening Tuberculosis Treatment.

针对结核分枝杆菌的严格反应作为缩短结核病治疗的策略。

• 发表时间: 2021
• 作者: Danchik, Carina;Wang, Siqing;Karakousis, Petros C
• 通讯作者: Karakousis, Petros C

Combination of a MIP3α-antigen fusion therapeutic DNA vaccine with treatments of IFNα and 5-Aza-2'Deoxycytidine enhances activated effector CD8+ T cells expressing CD11c in the B16F10 melanoma model.

MIP3α 抗原融合治疗性 DNA 疫苗与 IFNα 和 5-Aza-2 脱氧胞苷治疗的组合可增强 B16F10 黑色素瘤模型中表达 CD11c 的激活效应 CD8 T 细胞。

• 发表时间: 2023-08-14
• 作者: Fessler, Kaitlyn;Gordy, James T;Sandhu, Avinaash K;Hui, Yinan;Kapoor, Aakanksha R;Ayeh, Samuel K;Karanika, Styliani;Karakousis, Petros C;Markham, Richard B
• 通讯作者: Markham, Richard B

Modes of transmission of SARS-CoV-2 and evidence for preventive behavioral interventions.

SARS-CoV-2 的传播模式和预防性行为干预的证据。

• 发表时间: 2021-05-28
• 影响因子: 3.7
• 作者: Zhou, Lucas;Ayeh, Samuel K;Chidambaram, Vignesh;Karakousis, Petros C
• 通讯作者: Karakousis, Petros C