Targeting the Host to Treat TB: Inhibitors of Protein Kinase R

结核病是一种可治愈的传染病的唯一主要死亡原因，它是 由于耐药性的传播，逐渐变得无法治愈。该项目探索了一种 结核分枝杆菌(Mtb)对抗感染药物耐药性的解决办法：抑制蛋白激酶R (PKR)在宿主中。MTB依赖PKR导致全面疾病。我们最近发现 感染结核分枝杆菌的PKR缺陷小鼠显著减少细菌负荷和 组织病理学。这一机制涉及PKR在一定程度上限制 巨噬细胞通过干扰素-γ和微生物产物进行经典的激活。 蛋白酪氨酸激酶受体通过将干扰素γ信号与小分子的产生联系起来抑制巨噬细胞的激活 巨噬细胞失活因子白介素10(IL10)的含量。我们发现了一部小说 一种抑制PKR活性的抑制剂，可抑制PKR缺陷，从而产生“超激活” 巨噬细胞在干扰素γ或干扰素γ和结核分枝杆菌的组合中，反映如下 IL-10的产生减少，一氧化氮和肿瘤坏死因子的产生增加 (肿瘤坏死因子)。小分子巨噬细胞超激活剂(SAM)可以提供一种新的、辅助的 无药物选择潜力的慢性感染的治疗方法- 病原菌的抗药性。我们将探索Celgene丰富的激酶抑制剂文库，以 确定有效的、相对选择性的PKR抑制剂，并在体外将它们表征为自组装膜 在感染结核杆菌的小鼠中。

Tuberculosis is the single leading cause of death from a curable infectious disease and is becoming progressively incurable due to the spread of drug resistance. This project explores a work-around for resistance of M. tuberculosis (Mtb) to anti-infectives: inhibiting protein kinase R (PKR) in the host. Mtb depends on PKR to cause full-blown disease. We recently discovered that PKR-deficient mice infected with Mtb have markedly reduced bacterial burden and histopathology. The mechanism involves PKR's ability to restrain the extent to which macrophages undergo classical activation by interferon-gamma (IFNγ) and microbial products. PKR restrains macrophage activation by linking IFNγ signaling to the production of small amounts of interleukin-10 (IL10), a macrophage de-activating factor. We identified a novel inhibitor of PKR that phenocopied PKR deficiency in producing “super-activation” of macrophages in the presence of IFNγ or the combination of IFNγ and Mtb, as reflected by reduced production of IL10 and elevated production of nitric oxide and tumor necrosis factor (TNF). Small-molecule super-activators of macrophages (SAMs) could offer a novel, adjunctive approach to the treatment of chronic infections without the potential for selection of drug- resistance in the pathogen. We will explore Celgene's extensive library of kinase inhibitors to identify potent, relatively selective inhibitors of PKR and characterize them as SAMs in vitro and in Mtb-infected mice.