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

感染期间通过线粒体未折叠蛋白反应保护宿主的机制

• 批准号: 10220071
• 负责人: Mark Watson Pellegrino
• 金额: $ 37.22万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220071
• 关键词: Address; Adopted; Animal Model; Antibiotics; Caenorhabditis elegans; Cell physiology; Clinic; Development; Economics; Genetic Models; Homeostasis; Host Defense; Host resistance; Human; Immune response; Immunity; Infection; Infectious Agent; Inflammatory Response; Investigation; Mediating; Medical; Microbe; Mitochondria; Morbidity - disease rate; Natural Immunity; Outcome; Pathway interactions; Patients; Proteins; Pseudomonas aeruginosa; Reagent; Regulation; Research; Resistance to infection; Role; Stress; System; Therapeutic; antimicrobial; bacterial resistance; biological adaptation to stress; combat; drug resistant pathogen; host-microbe interactions; insight; mortality; novel; novel strategies; novel therapeutics; pathogen; pathogenic bacteria; preservation; response

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.

项目摘要 诊所中抗生素耐药病原体的兴起无疑是公认的医学关注点 这是全球人类和经济损失的巨大原因。进一步的警报是缺乏新的 治疗药物以对抗这些有害和潜在致命感染。因此，我们至关重要 生成新颖的方法来解决这个日益增长的问题。试剂的开发 增强宿主免疫可能是促进宿主抵抗感染的有效替代策略 通过减少病原体数量。另外，确定可以支持宿主容忍度的机制 承受有害微生物造成的损害，炎症反应同样至关重要。 线粒体具有多个必需的细胞功能，包括公认的作用 免疫反应。线粒体展开的蛋白质反应（UPRMT），一种应力激活途径 恢复线粒体功能，还通过 对先天免疫的调节。进一步研究调节和治疗潜力 因此，必须考虑其在保持线粒体稳态和 诱发抗微生物防御。当前的提案将在病原体中探索UPRMT 感染宿主和传染剂的调节机制的新机制。这里 我们将使用强大的遗传模型生物Caenorhabditis采用合并的方法 秀丽隐杆线虫和机会性细菌病原体铜绿假单胞菌，一种已建立的系统 宿主 - 微叶相互作用的研究。此外，我们将以我们目前的理解为基础 评估哺乳动物UPRMT在感染过程中促进宿主存活中的潜在作用。 总的来说，我们提出的研究计划的结果有望产生有关的新见解 感染过程中的UPRMT可能用于增强感染期间的宿主保护。