C-type Lectin Receptor Pathways in the Pathogenesis of TB/HIV Co-infection

C型凝集素受体通路在结核病/艾滋病毒双重感染发病机制中的作用

• 批准号: 10092516
• 负责人: Janice J Endsley
• 金额: $ 77.57万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092516
• 关键词: Animal Model; Anti-Inflammatory Agents; Autopsy; Biological; Biological Assay; Blood; C Type Lectin Receptors; Cause of Death; Cells; Cessation of life; Chemicals; Clinical; Complement; Cryopreservation; Data; Defect; Development; Disease; Disease Outcome; Disease model; Epidemic; Functional disorder; Genes; Genetic Transcription; HIV; HIV Infections; HIV/TB; Human; Immune; Immune System Diseases; Immune response; Immunology; Immunosuppression; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Intervention; Investigation; Lung; Lung Inflammation; Mediating; Modeling; Molecular; Molecular Biology; Mus; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmacotherapy; Phase; Positioning Attribute; Public Health; Publishing; Pulmonary Inflammation; Pulmonary Tuberculosis; Receptor Signaling; Relapse; Reporter; Research; Resolution; Role; Sampling; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Surface; System; T-Lymphocyte; Testing; Therapeutic; Tissue Banks; Tissues; Transcript; Tuberculosis; antiretroviral therapy; base; co-infection; cytokine; design; drug standard; gain of function; human subject; human tissue; humanized mouse; immune function; immunoregulation; in vivo; infection risk; insight; lung injury; macrophage; monocyte; mouse model; neutrophil; novel; repository; response; restoration; sample collection; therapeutic target; transcriptome; virology

Tuberculosis (TB) and Human immunodeficiency virus (HIV) cooperate to drive a deadly co-epidemic that results in approximately 12 million new infections and 4.5 million deaths annually. TB is the leading cause of death in people living with HIV infection, and the risk for new Mycobacterium tuberculosis (Mtb) infections and TB relapse continue despite restoration of T cells by anti-retroviral (ARV) therapy. A spectrum of immune dysfunction in human subjects with dual disease is well described, including both immune suppression and inappropriate inflammation. The mechanistic bases for many of these outcomes of co-infected individuals, however, are poorly understood and represent an important gap for development of host directed interventions to: 1) restore protective immune responses, 2) reduce pulmonary damage, and 3) complement standard drug therapy. We exploited our access to relevant human tissues and biologicals, and utilized our humanized mouse co-infection model, to identify novel candidate mechanisms for co-infection pathophysiology. As a result, we have preliminary data supporting an HIV-mediated effect to compromise the function of an immune-regulatory C-type lectin receptor in lung macrophages (Mɸ). The objective of this R01 application is to identify HIV-mediated defects in human Mɸ due to native and experimental infection, and demonstrate the impact of these defects in the setting of pulmonary TB. Our hypothesis is that that HIV modulates immunoregulatory CLRs in pulmonary Mɸ and compromises an important innate signaling pathway for recognition and resolution of tissue damaging inflammation in Mtb-infected lungs. We propose the following two aims to test this hypothesis: 1) Determine how compromise of immunoregulatory CLR pathways by HIV promotes pulmonary inflammation following Mtb infection, and 2) Identify mechanism(s) whereby HIV compromises CLR pathways as therapeutic targets to reduce inflammatory outcomes in Mtb/HIV co-infected lungs. These aims will be accomplished by using bio- banked biologicals and tissue from HIV+ donors, in vitro systems, gene deficient mice, and humanized mice. We are well positioned to carry out these studies as our interdisciplinary TB/HIV co-infection team includes immunology, pathology, molecular biology, animal model, and medicinal chemistry expertise. In phase I, we propose to demonstrate that HIV infection interferes with the anti-inflammatory function of MGL and demonstrate the consequences of MGL dysfunction in the Mtb-infected lung. In phase II, we will establish the mechanisms for HIV-mediated disturbance of MGL and explore novel CLR pathway targets as potential therapeutic approaches to reduce pulmonary damage in the setting of TB.

结核病(TB)和人类免疫缺陷病毒(HIV)合作推动了一种致命的共同流行病 每年造成约1200万新感染和450万人死亡。结核病是导致 艾滋病毒感染者的死亡，以及新的结核分枝杆菌(Mtb)感染和 尽管通过抗逆转录病毒(ARV)治疗恢复了T细胞，但结核病复发仍在继续。一种免疫的光谱 患有双重疾病的人类受试者的功能障碍得到了很好的描述，包括免疫抑制和 不适当的炎症。共同感染的个体的许多这些结果的机制基础， 然而，人们对这些问题了解甚少，这是发展以宿主为导向干预措施的一个重要差距 为了：1)恢复保护性免疫反应，2)减少肺损伤，3)补充标准药物 心理治疗。我们利用我们对相关人体组织和生物制品的接触，并利用我们的人源化小鼠 共同感染模型，以确定共同感染病理生理学的新候选机制。因此，我们 有初步数据支持艾滋病毒介导的影响，以损害免疫调节功能 肺巨噬细胞C型凝集素受体(M-ɸ)。这个R01应用程序的目标是识别HIV介导的 由于自然感染和实验感染导致的人Mɸ缺陷，并展示了这些缺陷对 肺结核病的发病环境。我们的假设是HIV调节肺组织中的免疫调节CLR Mɸ，并破坏了识别和解决组织损伤的一条重要的固有信号通路 结核分枝杆菌感染肺部的炎症。我们提出了以下两个目的来检验这一假设：1)确定如何 HIV对免疫调节CLR通路的破坏促进结核分枝杆菌感染后的肺部炎症 感染，以及2)确定艾滋病毒妥协CLR途径作为治疗靶点的机制(S) 减少结核分枝杆菌/艾滋病毒混合感染肺部的炎症结果。这些目标将通过使用生物- 储存来自HIV+捐献者、体外系统、基因缺陷小鼠和人源化小鼠的生物制品和组织。 我们有能力进行这些研究，因为我们的跨学科结核病/艾滋病毒联合感染团队包括 免疫学、病理学、分子生物学、动物模型和药物化学专业知识。在第一阶段，我们 建议演示HIV感染干扰MGL的抗炎功能并演示 结核分枝杆菌感染肺中MGL功能障碍的后果。在第二阶段，我们将建立机制 针对HIV介导的MGL的干扰，探索新的CLR通路靶点作为潜在的治疗手段 减少肺结核患者肺部损害的方法。