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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

基本信息

批准号：
10467029
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
项目类别：
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/10467029
关键词：
5&apos -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

项目摘要

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，是导致结核病的唯一主要原因当今世界死于传染病的人数最多。巨噬细胞是最常感染的宿主细胞。并最终负责确定接触结核分枝杆菌的结果是否为无感染、潜伏感染或活动性疾病。我们正在测试两种改善宿主对结核病控制的方法，这两种方法都涉及抑制靶标在巨噬细胞中，而不是在细菌中，期望这种宿主指导治疗(HDT)可与传统的抗分枝杆菌治疗(AMT)相结合，以缩短病程根治疗法。我们将检验以下假设。(1)Mtb的主机控制将被屏蔽 MTB诱导的巨噬细胞死亡。我们的初步证据支持以下具体假设：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死亡。(2)主机控制与干扰素-(干扰素)相比，通过增强巨噬细胞的激活，结核分枝杆菌也将受到青睐独自一人。我们的初步证据支持这样一种特定的假设，即这种增强是由一种小说所支持的，我们已经鉴定了一种类药物化合物，其作用导致抑制机制靶点雷帕霉素(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)提高巨噬细胞的存活率与其加强激活在改善结核分枝杆菌控制方面将是相加的或协同的，并且不会加剧免疫病理学如果由此导致的细菌负荷和抗原负荷的减少足够大的话。因此，我们将在感染结核分枝杆菌的小鼠身上单独和一起测试这两种HDTS，无论是否使用AMT。最后，我们假设宿主导向疗法(HDT)与抗分枝杆菌疗法(AMT)相结合将允许结核分枝杆菌感染小鼠无复发治愈的缩短治疗。目标1的重点是延长结核分枝杆菌感染的巨噬细胞处于健康状态，并确定阻断I型干扰素的机制信令会这样做。目标2的重点是增强存活的巨噬细胞的激活，并定义 MTOR和TFEB家族转录因子在此过程中的作用。目标3的作用是测试这两个相互结合以及与AMT相结合的干预措施。