Macrophage metabolism in diabetes and tuberculosis comorbidity

项目摘要/摘要 在结核病(TB)流行的国家，糖尿病患者的增加导致了糖尿病的重新出现。 糖尿病作为结核病严重危险因素的重要性。迫切需要实施结核病防治战略 预防和控制数百万接触结核分枝杆菌(Mtb)的糖尿病患者， 结核病的病原体。虽然众所周知糖尿病可以调节免疫反应，但大多数关于糖尿病的研究 肺结核-糖尿病共病主要集中在淋巴细胞功能的改变上。肺 巨噬细胞是第一批对结核分枝杆菌有反应的宿主细胞，被认为是最重要的宿主细胞之一。 决定疾病后果的细胞类型。我们之前的研究已经证明了肺 巨噬细胞代谢在促进或控制结核病的进展中起着关键作用。然而，无论是 糖尿病患者对结核病的易感性增加是由肺巨噬细胞代谢活动改变引起的 这几乎是未知的，因此代表着巨大的知识差距。组织驻留细胞的表型和功能 巨噬细胞在很大程度上受其环境中的营养物质水平的影响。考虑到糖尿病 导致慢性高血糖，这是导致糖尿病条件下结核病发展的关键因素，我们 假设由于高血糖环境，肺巨噬细胞的新陈代谢改变导致 糖尿病患者对结核病的易感性增加。我们将通过两个目标来检验这一假设：目标1.确定影响 结核分枝杆菌感染时高血糖对肺泡巨噬细胞代谢状态和通透性的影响。目标2. 询问高血糖如何影响肺结核患者肺巨噬细胞的异质性。我们将使用多个 学科方法，包括新陈代谢、基因组学和微生物学，以审问潜在的 从全新的角度探讨肺结核-糖尿病共病的发病机制。

Project Summary/Abstract The increase in diabetes patients in countries where tuberculosis (TB) is also endemic has led to the re-emerging importance of diabetes as a serious risk factor for TB. There is an urgent need to implement strategies for TB prevention and control among the millions of diabetes patients exposed to Mycobacterium tuberculosis (Mtb), the causative agent of TB. Although diabetes is known to modulate immune responses, most of the studies on TB-diabetes comorbidity have been primarily focused on the altered functions of lymphocytes. Lung macrophages are among the first host cells that respond to Mtb and are recognized as one of the most crucial cell types in determining the consequences of disease. Our previous work has demonstrated that lung macrophage metabolism plays a critical role in promoting or controlling the progression of TB. However, whether the increased susceptibility to TB in diabetes is caused by altered metabolic activities in lung macrophages is virtually unknown, thus representing a significant knowledge gap. The phenotype and functions of tissue-resident macrophages are greatly influenced by the level of nutrients in their environmental niches. Given that diabetes induces chronic hyperglycemia, a key factor that contributes to the development of TB in diabetic conditions, we hypothesize that the altered metabolism in lung macrophages, due to the hyperglycemic environment, leads to increased susceptibility to TB in diabetes. We will test this hypothesis with two aims: Aim 1. Determine the impact of hyperglycemia on the metabolic status and permissiveness of lung AMs during Mtb infection. Aim 2. Interrogate how hyperglycemia influences the heterogeneity of lung macrophages in TB. We will use multi- disciplinary approaches, including metabolism, genomics and microbiology to interrogate the underlying mechanism of TB-diabetes comorbidity from a completely novel perspective.