Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, The Netherlands.
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, The Netherlands.
PLoS Pathog. 2019 Apr 18;15(4):e1007724. doi: 10.1371/journal.ppat.1007724. eCollection 2019 Apr.
Type 2 diabetes mellitus (DM) is a major risk factor for developing tuberculosis (TB). TB-DM comorbidity is expected to pose a serious future health problem due to the alarming rise in global DM incidence. At present, the causal underlying mechanisms linking DM and TB remain unclear. DM is associated with elevated levels of oxidized low-density lipoprotein (oxLDL), a pathologically modified lipoprotein which plays a key role during atherosclerosis development through the formation of lipid-loaded foamy macrophages, an event which also occurs during progression of the TB granuloma. We therefore hypothesized that oxLDL could be a common factor connecting DM to TB. To study this, we measured oxLDL levels in plasma samples of healthy controls, TB, DM and TB-DM patients, and subsequently investigated the effect of oxLDL treatment on human macrophage infection with Mycobacterium tuberculosis (Mtb). Plasma oxLDL levels were significantly elevated in DM patients and associated with high triglyceride levels in TB-DM. Strikingly, incubation with oxLDL strongly increased macrophage Mtb load compared to native or acetylated LDL (acLDL). Mechanistically, oxLDL -but not acLDL- treatment induced macrophage lysosomal cholesterol accumulation and increased protein levels of lysosomal and autophagy markers, while reducing Mtb colocalization with lysosomes. Importantly, combined treatment of acLDL and intracellular cholesterol transport inhibitor (U18666A) mimicked the oxLDL-induced lysosomal phenotype and impaired macrophage Mtb control, illustrating that the localization of lipid accumulation is critical. Collectively, these results demonstrate that oxLDL could be an important DM-associated TB-risk factor by causing lysosomal dysfunction and impaired control of Mtb infection in human macrophages.
2 型糖尿病（DM）是发生结核病（TB）的主要危险因素。由于全球 DM 发病率的惊人上升，TB-DM 合并症预计将成为未来严重的健康问题。目前，将 DM 和 TB 联系起来的潜在因果机制尚不清楚。DM 与氧化型低密度脂蛋白（oxLDL）水平升高有关，oxLDL 是一种病理性修饰的脂蛋白，在动脉粥样硬化发展过程中通过形成富含脂质的泡沫巨噬细胞发挥关键作用，而这一事件也发生在 TB 肉芽肿的进展过程中。因此，我们假设 oxLDL 可能是将 DM 与 TB 联系起来的共同因素。为了研究这一点，我们测量了健康对照组、TB、DM 和 TB-DM 患者的血浆样本中的 oxLDL 水平，随后研究了 oxLDL 处理对人巨噬细胞感染结核分枝杆菌（Mtb）的影响。DM 患者的血浆 oxLDL 水平显著升高，并与 TB-DM 中的高甘油三酯水平相关。引人注目的是，与天然或乙酰化 LDL（acLDL）相比，oxLDL 孵育强烈增加了巨噬细胞 Mtb 负荷。从机制上讲，oxLDL-但不是 acLDL-处理诱导巨噬细胞溶酶体胆固醇积累并增加溶酶体和自噬标志物的蛋白水平，同时减少 Mtb 与溶酶体的共定位。重要的是，acLDL 和细胞内胆固醇转运抑制剂（U18666A）的联合处理模拟了 oxLDL 诱导的溶酶体表型并损害了巨噬细胞 Mtb 控制，表明脂质积累的定位至关重要。总的来说，这些结果表明，oxLDL 可能是一个重要的与 DM 相关的 TB 风险因素，通过引起溶酶体功能障碍和损害人巨噬细胞中 Mtb 感染的控制。
