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

结核病（TB）和人类免疫缺陷病毒（HIV）共同驱动致命的共同流行病， 导致每年约1 200万新感染和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）感染的风险， 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。免疫谱 在患有双重疾病的人类受试者中的功能障碍被充分描述，包括免疫抑制和 不适当的炎症共同感染个体的许多这些结果的机制基础， 而且是制定针对东道国干预措施的一个重要差距 目的：1）恢复保护性免疫反应，2）减少肺损伤，3）补充标准药物 疗法我们利用我们获得的相关人体组织和生物制品，并利用我们的人源化小鼠， 共感染模型，以确定新的候选机制的共感染病理生理学。结果我们 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（M φ）中的C型凝集素受体。本R 01申请的目的是识别HIV介导的 由于天然和实验性感染导致的人类M β缺陷，并证明这些缺陷对 肺结核的背景。我们的假设是HIV调节肺内免疫调节性CLRs， M蛋白和妥协的一个重要的先天信号通路的识别和解决组织损伤 结核分枝杆菌感染的肺部炎症。我们提出以下两个目标来检验这一假设：1）确定如何 HIV对免疫调节通路的损害促进了结核分枝杆菌感染后的肺部炎症 感染，和2）确定HIV损害作为治疗靶点的HIV途径的机制， 减少Mtb/HIV共感染肺部的炎症结果。这些目标将通过使用生物- 来自HIV+供体、体外系统、基因缺陷小鼠和人源化小鼠的库存生物制品和组织。 我们有能力开展这些研究，因为我们的跨学科结核病/艾滋病毒合并感染团队包括 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 建议证明HIV感染干扰MGL的抗炎功能，并证明 MGL功能障碍在结核分枝杆菌感染的肺中的后果。在第二阶段，我们将建立机制， 研究HIV介导的MGL紊乱，并探索新的MGL通路靶点作为潜在的治疗药物 减少肺结核患者肺损伤的方法。

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.