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

基本信息

批准号：
9538016
负责人：
Janice J Endsley
金额：
$ 74.83万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9538016
关键词：
Alveolar Macrophages Animal Model Anti-inflammatory Autopsy Biological Biological Assay Blood C Type Lectin Receptors Cause of Death Cells Cessation of life Chemicals Clinical Complement Data Defect Development Disease Disease Outcome Disease model Epidemic Functional disorder Genes Genetic Transcription HIV HIV Infections 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 Risk 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 insight lung injury macrophage monocyte mouse model neutrophil novel repository response restoration sample collection therapeutic target transcriptome virology

项目摘要

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 (M). The objective of this R01 application is to identify HIV-mediated defects in human M 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 M 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）合作推动致命的共同流动性每年导致大约1200万新感染和450万人死亡。结核病是主要原因艾滋病毒感染患者的死亡，以及新的结核分枝杆菌（MTB）感染的风险 TB继电器继续通过抗逆转录病毒（ARV）治疗对T细胞进行目的地恢复。一系列免疫有很好地描述了双重疾病受试者的功能障碍，包括免疫抑制和不当炎症。许多共同感染个体的这些结果的机械基础，但是，知之甚少，代表了开发宿主有定向干预措施的重要差距至：1）恢复受保护的免疫反应，2）减少肺损伤，3）完整的标准药物治疗。我们探索了对相关的人体组织和生物制剂的访问，并利用了人源化的小鼠共同感染模型，以识别用于共同感染病理生理学的新型候选机制。结果，我们具有支持HIV介导的效果的初步数据，以损害免疫调节的功能肺巨噬细胞中的C型凝集素受体（M）。该R01应用的目的是识别HIV介导的由于天然和实验性感染引起的人类M缺陷，并证明了这些缺陷在肺结核的设置。我们的假设是HIV调节肺中的免疫调节性CLR m并损害了重要的先天信号通路，以识别和解决组织破坏 MTB感染的肺部炎症。我们提出以下两个目的来检验这一假设：1）确定如何确定 HIV造成免疫调节CLR途径的折衷会促进MTB后肺部炎症感染和2）确定HIV损害CLR途径作为治疗靶标的机制减少MTB/HIV共感染肺的炎症结果。这些目标将通过使用生物来实现来自HIV+供体，体外系统，基因缺陷小鼠和人源化的小鼠的库存生物学和组织。由于我们的跨学科TB/HIV共同感染团队包括在第一阶段，我们提议证明HIV感染干扰了MGL的抗炎功能并证明 MTB感染的肺中MGL功能障碍的后果。在第二阶段，我们将建立机制用于MGL的HIV介导的灾难并探索新颖的CLR途径目标作为潜在疗法在结核病的情况下减少肺部损伤的方法。