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

项目摘要 无可否认，临床上耐药病原体的增加是一个公认的医学问题，因为 它是造成世界范围内巨大的人类和经济损失的原因。更令人担忧的是缺乏新的 与这些有害和潜在致命的感染作斗争的治疗方法。因此，至关重要的是，我们 制定新的方法来解决这一日益严重的问题。试剂盒的发展 增强宿主免疫力可能是提高宿主抵抗感染能力的有效替代策略 通过减少病原体数量。此外，确定可以支持宿主对 抵抗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，包括公认的在介导 免疫反应。线粒体未折叠蛋白反应(UPRmt)，一种应激激活途径 恢复线粒体功能，也参与宿主对感染的防御 调节先天免疫。进一步研究血管紧张素转换酶的调节和治疗潜力 因此，考虑到UPRmt在维护线粒体动态平衡和保护线粒体平衡方面的双重作用，UPRmt是有必要的 诱导抗微生物防御。目前的提案将在病原体的背景下探讨UPRmt 感染，以揭示宿主和病原体对其进行调控的新机制。这里 我们将使用一种组合的方法，使用强大的遗传模式生物--线虫 线虫和条件致病菌铜绿假单胞菌，一个建立在 研究宿主-微生物相互作用的学科。此外，我们将在目前的理解基础上，通过 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，我们提议的研究计划的结果预计将产生关于 UPRmt在感染期间可能被用来增强感染期间的宿主保护。

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.