Autophagy Against Tuberculosis and HIV

自噬对抗结核病和艾滋病毒

• 批准号: 9025642
• 负责人: VOJO P DERETIC
• 金额: $ 65.75万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025642
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Alleles; Antigen-Antibody Complex; Area; Autophagocytosis; Cells; Cessation of life; Clinical; Cytosol; Disease; Elements; Equilibrium; Funding; HIV; Health; Human; Immune; Immunity; Incidence; Individual; Infection; Infectious Agent; Inflammatory; Integration Host Factors; Interferon Type I; Knowledge; Learning; Lipids; Maintenance; Metabolism; Microbe; Molecular; Multi-Drug Resistance; Mycobacterium tuberculosis; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Pathogenesis; Pattern; Pharmaceutical Preparations; Physiological; Play; Population; Process; Prophylactic treatment; Public Health; Publishing; Regimen; Risk; Risk Factors; Role; Testing; Tuberculosis; Viral Proteins; Virus; Work; World Health Organization; base; co-infection; cytokine; drug development; killings; latent infection; macrophage; novel strategies; novel therapeutics; nutrition; outcome forecast; pandemic disease; pathogen; prevent; prophylactic; response; therapy development; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS) are diseases of exceptional public health significance. Their importance is further heightened by the global TB-AIDS co-pandemic. A co-infection with the respective etiologic agents, Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) alters the course of diseases caused by each infectious agent alone. Typically, only 10% of Mtb infections progress to clinically active TB in the absence of HIV. Instead, a controlled, long lasting asymptomatic infection, referred to as latent TB infection (LTBI), is established. Establishment of LTBI and the drivers of progression to active disease are not fully understood. Previously untried approaches are needed to move the field forward. In this application, we will take a new approach by demonstrating the key role of autophagy in maintaining the balance between LTBI and progression to active TB, and as a process targeted by the virus during HIV-Mtb co-infection. Autophagy is a newly recognized but nevertheless evolutionary ancient innate immunity mechanism that acts as a cell-autonomous defense against a variety of intracellular pathogens including Mtb. Our published work and studies by others indicate that autophagy, when appropriately induced, is a significant anti-Mtb cell- autonomous innate immunity defense. We propose that autophagy prevents progression to active disease and favors LTBI. The host-protective action is based on two effector functions of autophagy: first, it eliminates intracellulr Mtb, and, second, it suppresses pathogenic cytokine responses. In this project, we will test the hypothesis that autophagy maintains a host-protective state and prevents progression to active TB, whereas intrinsic host factors or HIV co-infection interfere with autophagy and promote clinically overt TB. If this hypothesis is correct, pharmacological targeting of autophagy and specific processes identified in this project will provide new prophylactic and treatment opportunities. The specific aims of this application are: Specific Aim 1. Determine whether and how HIV interferes with autophagic elimination of Mtb in co- infected macrophages. Mechanistically, we will define the role of the HIV protein Nef and its alleles from clinical HIV isolates and test their capacity to inhibit Beclin 1-dependent autophagy and suppress Mtb elimination in macrophages. Specific Aim 2. Determine whether and how autophagy inhibits type I interferon (IFN) responses associated with progression to active disease. We will test whether autophagy prevents induction of type I IFN associated with active TB, and how this affects TB pathogenesis. Specific Aim 3. Define whether and how cellular neutral lipid loads affect autophagic control of Mtb. To determine how intrinsic host factors (in the absence of HIV) influence autophagy's ability to maintain a host- protective state-i.e. the LTBI status-we will tes whether host cell lipid stores and imbalances in cellular lipid loads affect autophagic control of Mtb.

描述（由申请人提供）： 结核病（TB）和获得性免疫缺陷综合症（艾滋病）是具有特殊公共卫生意义的疾病。全球结核病与艾滋病的共同流行进一步凸显了它们的重要性。结核分枝杆菌 (Mtb) 和人类免疫缺陷病毒 (HIV) 等各自病原体的共同感染会改变每种病原体单独引起的疾病进程。通常，在没有 HIV 的情况下，只有 10% 的 Mtb 感染会进展为临床活动性结核病。相反，建立了一种受控的、长期持续的无症状感染，称为潜伏性结核感染（LTBI）。 LTBI 的建立和 进展为活动性疾病的驱动因素尚不完全清楚。需要以前未尝试过的方法来推动该领域的发展。在此应用中，我们将采取一种新方法，证明自噬在维持 LTBI 和发展为活动性结核病之间的平衡中的关键作用，以及作为 HIV-Mtb 合并感染期间病毒的目标过程。自噬是一种新近认识的、但仍然是进化的古老先天免疫机制，可作为细胞自主防御机制，对抗包括结核分枝杆菌在内的多种细胞内病原体。我们发表的工作和其他人的研究表明，当适当诱导时，自噬是一种重要的抗 Mtb 细胞自主先天免疫防御。我们认为自噬可以防止进展为活动性疾病并有利于 LTBI。宿主保护作用基于自噬的两个效应子功能：首先，它消除细胞内的 Mtb，其次，它抑制致病性细胞因子反应。在本项目中，我们将检验以下假设：自噬维持宿主保护状态并防止进展为活动性结核病，而内在宿主因素或 HIV 合并感染会干扰自噬并促进临床上明显的结核病。如果这一假设正确，那么本项目中确定的自噬和特定过程的药理学靶向将提供新的预防和治疗机会。本申请的具体目标是： 具体目标 1. 确定 HIV 是否以及如何干扰共感染巨噬细胞中 Mtb 的自噬消除。从机制上讲，我们将定义 HIV 蛋白 Nef 及其来自临床 HIV 分离株的等位基因的作用，并测试它们抑制 Beclin 1 依赖性自噬和抑制巨噬细胞中 Mtb 消除的能力。具体目标 2. 确定自噬是否以及如何抑制与活动性疾病进展相关的 I 型干扰素 (IFN) 反应。我们将测试自噬是否会阻止与活动性结核病相关的 I 型干扰素的诱导，以及这如何影响结核病的发病机制。具体目标 3. 确定细胞中性脂质负荷是否以及如何影响 Mtb 的自噬控制。确定内在宿主因素（在没有 HIV 的情况下）如何影响自噬维持宿主保护状态的能力，即LTBI 状态——我们将测试宿主细胞脂质储存和细胞脂质负荷不平衡是否影响 Mtb 的自噬控制。