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

描述（由申请人提供）：结核病是可治愈传染病的唯一主要原因，并且由于耐药性的蔓延而逐渐变得无法治愈。该项目探索了一种解决结核分枝杆菌 (Mtb) 抗感染药物耐药性的方法：抑制宿主体内的蛋白激酶 R (PKR)。 Mtb 依赖 PKR 来引起全面的疾病。我们最近发现，感染 Mtb 的 PKR 缺陷小鼠的细菌负荷和组织病理学显着降低。该机制涉及 PKR 抑制巨噬细胞经历干扰素-γ (IFN?) 和微生物产物经典激活程度的能力。 PKR通过连接IFN抑制巨噬细胞活化？产生少量白细胞介素 10 (IL10)（一种巨噬细胞失活因子）的信号传导。我们发现了一种新型 PKR 抑制剂，它可以模仿 PKR 缺陷，在存在 IFN 的情况下产生巨噬细胞的“超级激活”？或者联合干扰素？和 Mtb，如 IL10 产生减少和一氧化氮和肿瘤坏死因子 (TNF) 产生增加所反映。巨噬细胞小分子超级激活剂（SAM）可以为慢性感染的治疗提供一种新颖的辅助方法，而无需选择病原体的耐药性。我们将探索 Celgene 广泛的激酶抑制剂库，以鉴定有效的、相对选择性的 PKR 抑制剂，并在体外和 Mtb 感染的小鼠中将它们表征为 SAM。

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.