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

结核病是可治愈的传染病导致死亡的唯一主要原因， 由于耐药性的扩散而逐渐变得无法治愈。该项目探讨了 M的电阻的变通方法。抗感染药物：抑制蛋白激酶R (PKR)在主机。结核分枝杆菌依赖PKR引起全面疾病。我们最近发现 感染Mtb的PKR缺陷小鼠的细菌负荷显著降低， 组织病理学该机制涉及PKR的能力，以抑制的程度， 巨噬细胞经历干扰素-γ（IFNγ）和微生物产物的经典活化。 PKR通过将IFNγ信号传导与小分子的产生联系起来来抑制巨噬细胞活化 量的白细胞介素-10（IL 10），一种巨噬细胞失活因子。我们发现了一本小说 PKR抑制剂，其表型模仿PKR缺陷， 巨噬细胞在IFNγ或IFNγ和Mtb的组合的存在下，如通过 IL 10的产生减少，一氧化氮和肿瘤坏死因子的产生增加 （TNF）。小分子巨噬细胞超活化剂（SAM）可以提供一种新的， 治疗慢性感染的方法，而没有选择药物的可能性- 病原体的抵抗力我们将探索Celgene广泛的激酶抑制剂库， 鉴定PKR的有效的、相对选择性的抑制剂，并将它们表征为体外SAM， 在结核分枝杆菌感染的小鼠中。

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.