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

描述（由申请人提供）：结核病是一种可治愈的传染病导致死亡的唯一主要原因，由于耐药性的蔓延，结核病正逐渐变得无法治愈。本项目探讨了结核分枝杆菌（Mtb）对抗感染药物耐药的一种解决方法：抑制宿主中的蛋白激酶R （PKR）。结核分枝杆菌依靠PKR引起全面的疾病。我们最近发现，感染Mtb的pkr缺陷小鼠明显减少了细菌负担和组织病理学。其机制涉及PKR抑制巨噬细胞受干扰素- γ (IFN?)和微生物产物经典激活的程度。PKR通过连接IFN抑制巨噬细胞活化信号传导产生少量的白细胞介素-10 (IL10)，一种巨噬细胞去活因子。我们发现了一种新的PKR抑制剂，在IFN存在的情况下，它在巨噬细胞产生“超激活”时表型PKR缺陷。还是IFN的组合？和结核分枝杆菌，通过降低il - 10的产生和提高一氧化氮和肿瘤坏死因子（TNF）的产生来反映。巨噬细胞的小分子超激活剂（SAMs）可以为慢性感染的治疗提供一种新的辅助方法，而不会在病原体中选择耐药性。我们将探索Celgene广泛的激酶抑制剂文库，以鉴定有效的、相对选择性的PKR抑制剂，并在体外和mtb感染小鼠中将其定性为SAMs。

DESCRIPTION (provided by applicant): 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 (IFN?) and microbial products. PKR restrains macrophage activation by linking IFN? 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 IFN? or the combination of IFN? 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.