Host-directed therapy of tuberculosis: Rescuing macrophages and enhancing their activation

结核病的宿主导向治疗：拯救巨噬细胞并增强其活化

• 批准号: 10241485
• 负责人: CARL Francis NATHAN
• 金额: $ 74.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241485
• 关键词: 5' -AMP-activated protein kinase; ATP phosphohydrolase; Abbreviations; Aerosols; Antibodies; Aspartate; Autophagocytosis; BHLH Protein; Bacteria; Binding; Biogenesis; Birth; Bone Marrow; Cause of Death; Cell Death; Cells; Cessation of life; Chemicals; Chemistry; Collaborations; Communicable Diseases; Cyclic GMP; Disease; Elements; Ensure; Exposure to; Extracellular Signal Regulated Kinases; FOXO3A gene; FRAP1 gene; Family; Fingers; Fostering; Genes; Goals; Host Defense; Human; IFNAR1 gene; Immune; Immune system; Impairment; In Vitro; Infection; Interferon Type I; Interferon-alpha; Interferons; Intervention; Knock-out; Life Cycle Stages; Lung; MAP Kinase Gene; Macrophage Activation; Mitogen-Activated Protein Kinases; Monoclonal Antibodies; Mus; Mycobacterium tuberculosis; Myeloid Cells; NOS2A gene; Outcome; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphotransferases; Predisposition; Production; Proto-Oncogene Proteins c-akt; Proton Pump; Reactive Nitrogen Species; Regimen; Regulation; Relapse; Resistance; Ribosomal Protein S6 Kinase; Rifampin; Role; Self-control as a personality trait; Signal Transduction; TFE3 gene; Testing; Tuberculosis; activating transcription factor; antimicrobial; autocrine; chemotherapy; curative treatments; drug development; expectation; immunopathology; improved; intraperitoneal; latent infection; macrophage; mycobacterial; novel therapeutics; phosphoric diester hydrolase; premature; promoter; receptor; small molecule; transcription factor; tuberculosis drugs; tuberculosis treatment

Mycobacterium tuberculosis (Mtb) is a bacterium that causes tuberculosis (TB), the single leading cause of death in the world from infectious disease today. The macrophage is the host cell most commonly infected by Mtb and ultimately responsible for determining whether the outcome of exposure to Mtb is no infection, latent infection or active disease. We are testing two ways to improve the host's control of TB, both of which involve inhibiting targets in the macrophage, rather than in the bacterium, with the expectation that such host-directed therapies (HDT) can be combined with conventional anti-mycobacterial therapy (AMT) to shorten the course of curative treatment. We will test the following hypotheses. (1) Host control of Mtb will be favored by blocking Mtb-induced death of macrophages. Our preliminary evidence supports the specific hypothesis that Mtb- induced death of macrophages is exacerbated by the autocrine action of type I interferon. (2) Host control of Mtb will also be favored by enhancing macrophage activation over the level achieved with interferon- (IFN) alone. Our preliminary evidence supports the specific hypothesis that such enhancement is favored by a novel, drug-like chemical compound we have identified whose action leads to inhibition of mechanistic target of rapamycin (mTOR), resulting in the activation of certain transcription factors, including TFEB, that promote lysosomal biogenesis and autophagy. (3) The combination of enhanced survival of macrophages and their enhanced activation will be additive or synergistic in improving the control of Mtb and will not exacerbate immunopathology if the resulting reduction in bacterial burden and antigenic load is great enough. Accordingly, we will test the two HDTs alone and together in Mtb-infected mice, with and without AMT. Finally, we hypothesize that host-directed therapy (HDT) combined with anti-mycobacterial therapy (AMT) will allow treatment-shortening for relapse-free cure of Mtb-infected mice. The focus of Aim 1 is to prolong the survival of Mtb-infected macrophages in a healthy state and to define the mechanisms by which blockade of type I IFN signaling does so. The focus of Aim 2 is to enhance the activation of surviving macrophages and to define the role of mTOR and TFEB family transcription factors in doing so. The role of Aim 3 is to test these two interventions in combination with each other and with AMT.

结核分枝杆菌（Mtb）是一种引起结核病（TB）的细菌，结核病是结核病的单一主要原因。 死于传染病的人数。巨噬细胞是最常见的感染宿主细胞， 并最终负责确定暴露于Mtb的结局是否为无感染、潜伏 感染或活动性疾病。我们正在测试两种方法来改善宿主对结核病的控制，这两种方法都涉及 抑制巨噬细胞中的靶点，而不是细菌中的靶点，期望这种宿主定向的 治疗（HDT）可以与传统的抗分枝杆菌治疗（AMT）相结合，以缩短病程。 治愈性治疗我们将检验以下假设。(1)Mtb的主机控制将通过阻止而受到青睐 结核杆菌诱导的巨噬细胞死亡。我们的初步证据支持特定的假设，即结核分枝杆菌- I型干扰素的自分泌作用加剧了巨噬细胞的诱导死亡。(2)的主控 结核分枝杆菌也将有利于增强巨噬细胞活化的水平与干扰素β（IFN β）实现的. 一个人我们的初步证据支持这样一个特定的假设，即这种增强受到一种新的， 我们已经鉴定了一种药物样化合物，其作用导致抑制 雷帕霉素（mTOR），导致某些转录因子的激活，包括TFEB，促进 溶酶体生物发生和自噬。(3)巨噬细胞存活率的提高及其 增强的活化在改善Mtb的控制方面将是加和的或协同的， 如果细菌负荷和抗原负荷的减少足够大，则免疫病理学也是如此。因此，委员会认为， 我们将在有和没有AMT的Mtb感染小鼠中单独和一起测试两种HDT。最后我们 假设宿主导向治疗（HDT）联合抗分枝杆菌治疗（AMT）将允许 治疗缩短，用于Mtb感染小鼠的无复发治愈。目标1的重点是延长 结核分枝杆菌感染的巨噬细胞在健康状态，并确定机制，通过阻断I型干扰素 信号就是这样做的。目的2的重点是增强存活巨噬细胞的活化，并确定巨噬细胞的活化机制。 mTOR和TFEB家族转录因子在其中的作用。Aim 3的作用是测试这两个 干预措施相互结合，并与AMT。