Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada.
Front Immunol. 2021 Jul 8;12:702142. doi: 10.3389/fimmu.2021.702142. eCollection 2021.
The global antimicrobial resistance crisis poses a significant threat to humankind in the coming decades. Challenges associated with the development of novel antibiotics underscore the urgent need to develop alternative treatment strategies to combat bacterial infections. Host-directed therapy is a promising new therapeutic strategy that aims to boost the host immune response to bacteria rather than target the pathogen itself, thereby circumventing the development of antibiotic resistance. However, host-directed therapy depends on the identification of druggable host targets or proteins with key functions in antibacterial defense. Protein Kinase R (PKR) is a well-characterized human kinase with established roles in cancer, metabolic disorders, neurodegeneration, and antiviral defense. However, its role in antibacterial defense has been surprisingly underappreciated. Although the canonical role of PKR is to inhibit protein translation during viral infection, this kinase senses and responds to multiple types of cellular stress by regulating cell-signaling pathways involved in inflammation, cell death, and autophagy - mechanisms that are all critical for a protective host response against bacterial pathogens. Indeed, there is accumulating evidence to demonstrate that PKR contributes significantly to the immune response to a variety of bacterial pathogens. Importantly, there are existing pharmacological modulators of PKR that are well-tolerated in animals, indicating that PKR is a feasible target for host-directed therapy. In this review, we provide an overview of immune cell functions regulated by PKR and summarize the current knowledge on the role and functions of PKR in bacterial infections. We also review the non-canonical activators of PKR and speculate on the potential mechanisms that trigger activation of PKR during bacterial infection. Finally, we provide an overview of existing pharmacological modulators of PKR that could be explored as novel treatment strategies for bacterial infections.
全球抗菌药物耐药性危机在未来几十年对人类构成重大威胁。新型抗生素开发所面临的挑战突显了开发替代治疗策略来对抗细菌感染的迫切需要。宿主导向治疗是一种有前途的新治疗策略，旨在增强宿主对细菌的免疫反应，而不是针对病原体本身，从而避免抗生素耐药性的产生。然而，宿主导向治疗依赖于识别可药物化的宿主靶标或在抗菌防御中具有关键功能的蛋白质。蛋白激酶 R (PKR) 是一种已被充分研究的人类激酶，在癌症、代谢紊乱、神经退行性疾病和抗病毒防御中具有既定作用。然而，它在抗菌防御中的作用却令人惊讶地被低估了。虽然 PKR 的典型作用是在病毒感染期间抑制蛋白质翻译，但这种激酶通过调节涉及炎症、细胞死亡和自噬的细胞信号通路来感知和应对多种类型的细胞应激——所有这些机制对于宿主针对细菌病原体的保护性反应都是至关重要的。事实上，越来越多的证据表明，PKR 对多种细菌病原体的免疫反应有重要贡献。重要的是，已经有针对 PKR 的药理学调节剂，这些调节剂在动物中耐受良好，表明 PKR 是宿主导向治疗的一个可行靶点。在这篇综述中，我们提供了 PKR 调节的免疫细胞功能概述，并总结了目前关于 PKR 在细菌感染中的作用和功能的知识。我们还回顾了 PKR 的非典型激活剂，并推测了在细菌感染过程中触发 PKR 激活的潜在机制。最后，我们概述了现有的 PKR 药理学调节剂，它们可以作为细菌感染的新治疗策略进行探索。
Zotero 插件