Mechanisms of host protection during infection via the mitochondrial unfolded protein response

项目摘要 抗生素耐药性病原体在临床中的增加是公认的医学问题， 它是全世界巨大的人类和经济损失的原因。更令人担忧的是， 治疗，以对抗这些有害的和潜在的致命感染。因此，我们必须 产生新的方法来解决这个日益严重的问题。试剂的开发， 增强宿主免疫力可能是促进宿主抵抗感染的有效替代策略 减少病原体数量此外，确定能够支持宿主耐受性的机制， 抵御有害微生物造成的损害和炎症反应同样重要。 线粒体具有多种基本的细胞功能，包括在介导线粒体的细胞增殖中的公认作用。 免疫反应线粒体未折叠蛋白反应（UPRmt），一种应激激活的途径 恢复线粒体功能，也参与宿主对感染的防御， 调节先天免疫。进一步研究的调节和治疗潜力， 因此，考虑到UPRmt在维持线粒体稳态和维持线粒体内环境稳定方面的双重作用， 诱导抗微生物防御目前的提案将在病原体的背景下探索UPRmt 感染，以揭示其调节宿主和感染因子的新机制。这里 我们将使用强大的遗传模式生物小杆线虫， 线虫和条件性细菌病原体铜绿假单胞菌，一个建立的系统， 宿主与微生物相互作用的研究。此外，我们将在现有认识的基础上， 评估哺乳动物UPRmt在感染期间促进宿主存活的潜在作用。 总的来说，我们提出的研究计划的结果预计将产生新的见解， UPRmt在感染过程中，可能会被用来增强主机的保护感染。

Project Summary The rise of antibiotic resistant pathogens in the clinic is undeniably a recognized medical concern since it is the cause of enormous human and economic loss worldwide. Of further alarm is the lack of new therapeutics to combat these harmful and potentially deadly infections. Accordingly, it is critical that we generate novel approaches to address this growing problem. The development of reagents that enhance host immunity may be an effective alternative strategy to promote host resistance to infection by reducing pathogen numbers. In addition, identifying mechanisms that can support host tolerance to withstand the damage inflicted by harmful microbes and the inflammatory response is equally as vital. Mitochondria have multiple essential cellular functions including a recognized role in mediating the immune response. The mitochondrial unfolded protein response (UPRmt), a stress-activated pathway that recovers mitochondrial function, also participates in host defense against infection through the regulation of innate immunity. Further investigation into the regulation and therapeutic potential of the UPRmt is therefore warranted considering its dual roles in preserving mitochondrial homeostasis and inducing anti-microbial defense. The current proposal will explore the UPRmt in the context of pathogen infection to uncover novel mechanisms of its regulation by both the host and the infectious agent. Here we will employ a combined approach using the powerful genetic model organism Caenorhabditis elegans and the opportunistic bacterial pathogen Pseudomonas aeruginosa, an established system in the study of host-microbe interactions. Moreover, we will build on our current understanding by evaluating the potential role of the mammalian UPRmt in promoting host survival during infection. Collectively, the outcomes from our proposed research plan are expected to yield novel insights of the UPRmt during infection that potentially may be used to enhance host protection during infection.