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：
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
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/10241485
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）是导致结核病（TB）的细菌，这是单一的主要原因当今传染病的世界死亡。巨噬细胞是最常见的宿主细胞 MTB，最终负责确定接触MTB的结果是否没有感染，潜在感染或活动疾病。我们正在测试两种方法来改善宿主对结核病的控制，这两者都涉及。抑制巨噬细胞中的靶标，而不是细菌中的靶标，并期望这种宿主定向疗法（HDT）可以与常规的抗细菌疗法（AMT）结合使用，以缩短治疗治疗。我们将检验以下假设。（1）通过阻止，将首选MTB的主机控制 MTB诱导的巨噬细胞死亡。我们的初步证据支持MTB-的具体假设 I型干扰素的自分泌作用加剧了巨噬细胞的诱发死亡。（2）主机控制 MTB也将通过增强巨噬细胞激活比Interferon-达到的水平（IFN）优先。独自的。我们的初步证据支持以下特定假设，即这种增强是由小说所青睐的我们已经确定了类似药物的化学化合物，其作用导致抑制机械靶标的雷帕霉素（MTOR），导致某些转录因子（包括TFEB）的激活溶酶体生物发生和自噬。（3）增强巨噬细胞生存的结合及其增强的激活将在改善MTB的控制方面添加或协同作用，并且不会加剧免疫病理学，如果导致细菌燃烧和抗原负荷的减少足够好。根据我们将单独测试两个HDT，并在MTB感染的小鼠中共同测试和无AMT。最后，我们假设宿主指导的治疗（HDT）与抗菌治疗（AMT）相结合将允许用于MTB感染的小鼠的无浮力治疗的治疗缩短。目标1的重点是延长在健康状态下感染的MTB感染的巨噬细胞，并定义了I型IFN封锁的机制信号这样做。目标2的重点是增强幸存的巨噬细胞的激活并定义 MTOR和TFEB家族转录因子的作用在此过程中。目标3的作用是测试这两个干预措施相互结合，与AMT结合。