Role of stearoyl-CoA desaturase 2 in macrophage-mediated antimicrobial immunity

摘要 尿路感染(UTIs)主要由致尿性大肠杆菌(UPEC)引起，其发病率较高 老年妇女复发，是一个主要的健康问题。尽管有许多因素导致了这一点 易感性增加，与年龄相关的巨噬细胞功能改变也可能起作用。巨噬细胞 先天免疫细胞被招募为第一反应者，通过以下方式帮助控制感染：识别和 内化病原体以进行降解；提供抗原以招募适应性免疫反应；以及 协调组织炎症。先前的研究表明，巨噬细胞功能失调。 年龄增长的部分原因是脂类内环境的紊乱。例如，脂肪酸去饱和酶 硬脂酰辅酶A去饱和酶2(SCD2)随着年龄的增长而下调。然而，SCD2在维持 巨噬细胞在感染中的作用尚不清楚。初步数据表明SCD2基因缺失 巨噬细胞清除内化的UPEC的能力较差，可能是由于自噬小体的缺陷。 降解和线粒体功能。提出了SCD2缺失改变血脂的模型。 细胞膜的组成，从而扰乱依赖于膜的过程，如 自噬小体与溶酶体融合以通过内部线粒体进行降解或细胞呼吸 薄膜。因此，Aim 1将在体外研究SCD2缺陷的巨噬细胞，以进一步阐明这些缺陷 增加UPEC感染易感性的细胞和分子过程。目标2将决定是否 在UTI小鼠模型中，巨噬细胞SCD2在宿主对UPEC感染的反应中起重要作用。 这项研究的完成将提供对SCD2介导的脂质的机制的更深层次的理解 新陈代谢维持基本的巨噬细胞免疫功能，这是一个重要的知识缺口，仍然存在 这一领域，以及扩大现有的理解巨噬细胞的脂肪代谢和衰老。 此外，这项工作可能会为老年人复发性尿路感染的临床治疗提供新的策略， 治疗仍不充分的疾病。加上以学生为中心的培训计划和严格但 在协作研究环境下，拟议的研究还将使私人投资公司能够扩展现有的和获得 新的技术、科学和专业技能将是成为独立调查员的关键。至 进一步加强培训，包括整合临床活动和为过渡做好准备的战略 进入他们职业生涯的下一个阶段。

ABSTRACT Urinary tract infections (UTIs) predominantly caused by uropathogenic E. coli (UPEC) have a high rate of recurrence in elderly women, a major health problem. Though there are many factors that contribute to this increased susceptibility, age-related changes in macrophage function may also play a role. Macrophages are innate immune cells that are recruited as first responders to help control infection by: recognizing and internalizing pathogens for degradation; presenting antigens to recruit the adaptive immune response; and orchestrating tissue inflammation. Previous studies have demonstrated that macrophages become dysfunctional with age due in part to perturbations in lipid homeostasis. For instance, the fatty acid-desaturating enzyme stearoyl-CoA desaturase 2 (SCD2) becomes downregulated with age. However, the role of SCD2 in maintaining macrophage functions in infection is not clearly understood. Preliminary data indicate that SCD2-deficient macrophages are less able to eliminate internalized UPEC, perhaps due to deficits in autophagosome degradation and mitochondrial function. A model is proposed by which deficiency of SCD2 alters the lipid composition of cellular membranes thereby disrupting membrane-dependent processes, such as autophagosome fusion with lysosomes for degradation or cellular respiration across the inner mitochondrial membrane. Therefore, aim 1 will study SCD2-deficient macrophages in vitro to further elucidate these defective cellular and molecular processes that increase susceptibility to UPEC infection. Aim 2 will determine whether macrophage SCD2 plays an important role in the host response to UPEC infection in a mouse model of UTI. Completion of this study will provide a deeper understanding of the mechanism by which SCD2-mediated lipid metabolism maintains fundamental macrophage immune functions, an important knowledge gap that remains in the field, as well as expand on the existing understanding of lipid metabolism in macrophages and aging. Additionally, this work may reveal novel strategies for the clinical management of recurrent UTIs in the elderly, for which treatments remain inadequate. Together with a student-focused training plan and rigorous but collaborative research environment, the proposed study will also enable the PI to extend existing and acquire new technical, scientific, and professional skills that will be key to becoming an independent investigator. To further enhance training, a strategy is included to integrate clinical activities and prepare the PI for transitioning to the next stage of their career.