Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
PLoS One. 2012;7(2):e30512. doi: 10.1371/journal.pone.0030512. Epub 2012 Feb 16.
Host factors that microbial pathogens exploit for their propagation are potential targets for therapeuic countermeasures. No host enzyme has been identified whose genetic absence benefits the intact mammalian host in vivo during infection with Mycobacterium tuberculosis (Mtb), the leading cause of death from bacterial infection. Here, we report that the dsRNA-dependent protein kinase (PKR) is such an enzyme. PKR-deficient mice contained fewer viable Mtb and showed less pulmonary pathology than wild type mice. We identified two potential mechanisms for the protective effect of PKR deficiency: increased apoptosis of macrophages in response to Mtb and enhanced activation of macrophages in response to IFN-gamma. The restraining effect of PKR on macrophage activation was explained by its mediation of a previously unrecognized ability of IFN-gamma to induce low levels of the macrophage deactivating factor interleukin 10 (IL10). These observations suggest that PKR inhibitors may prove useful as an adjunctive treatment for tuberculosis.
宿主因素是微生物病原体繁殖所利用的潜在治疗靶点。在感染结核分枝杆菌（Mtb）时，尚未发现任何宿主酶的遗传缺失对完整的哺乳动物宿主有益，Mtb 是细菌性感染的主要死亡原因。在这里，我们报告 dsRNA 依赖性蛋白激酶（PKR）就是这样一种酶。PKR 缺陷型小鼠中存活的 Mtb 较少，肺部病理变化也比野生型小鼠少。我们确定了 PKR 缺乏的两种潜在保护机制：对 Mtb 反应的巨噬细胞凋亡增加和对 IFN-γ反应的巨噬细胞激活增强。PKR 对巨噬细胞激活的抑制作用可以通过其介导 IFN-γ诱导低水平的巨噬细胞失活因子白细胞介素 10（IL10）来解释。这些观察结果表明，PKR 抑制剂可能作为治疗结核病的辅助治疗方法很有用。
