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

摘要

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.