Foam cells as drug targets in tuberculosis

富含脂质的巨噬细胞(泡沫细胞)是维持慢性结核病(TB)感染的核心。泡沫细胞 为结核分枝杆菌的生存提供了有利的生态位，因为抗菌功能 在这些细胞中普遍下调。此外，泡沫细胞会导致组织损伤和干酪化，从而促进 结核病传播。事实上，结核病引起的组织损害的程度与泡沫细胞的丰度密切相关。 在病变部位。这一建议的主要假设是，阻止泡沫细胞的形成将有助于 巨噬细胞对结核分枝杆菌感染的清除作用。我们最近发现，与胆固醇不同- 在结核的动脉粥样硬化病变、富含泡沫细胞的区域和坏死区发现富酯泡沫细胞 肉芽肿富含甘油三酯。鉴于储存脂的不同性质，潜在的 结核泡沫细胞中的脂质堆积机制必须与已知发生的机制有很大不同 在动脉粥样硬化形成过程中。因此，需要针对结核病的干预措施来阻止结核病中泡沫细胞的形成。感染 结核分枝杆菌与甘油三酯相关的两条细胞通路的失调有关 动态平衡：第一种是促脂肪生成的，包括两种激酶，蛋白激酶B和mTOR复合体1 (AKT/mTORC1)；第二个是抗脂蛋白，包括AMP激活的蛋白激酶和NAD-1。 依赖性脱乙酰酶称为sirtuins(AMPK/SIRT)。我们提出了一个两个目标的计划，利用来自 人供体和实验感染巨噬细胞和产生坏死性的小鼠品系 肺结核病变(C3HeB/FEJ)。这些实验将表征：(I)抗脂肪生成的效果 体外感染人巨噬细胞抗分枝杆菌功能的治疗；(Ii) 这些途径的激活和临床结核分枝杆菌感染的控制；以及(Iii)抗脂作用 C3HeB/FEJ小鼠结核病的辅助治疗。这项提案的总体目标是发现 促脂肪生成和抗脂肪生成途径中的可用药靶点，长期目标是缩短 结核病治疗持续时间和改善结核病相关免疫病理学。这项提议预计将导致临床 新型宿主导向疗法治疗结核病的试验。更广泛地说，这些研究预计将揭示 针对非动脉粥样硬化患者适应不良的巨噬细胞反应的药物干预的可能性 并刺激他们的追求。

Lipid-laden macrophages (foam cells) are central to maintaining chronic tuberculosis (TB) infection. Foam cells provide a favorable niche for survival of Mycobacterium tuberculosis, because antimicrobial functions are generally down-regulated in these cells. Moreover, foam cells induce tissue damage and caseation, and facilitate TB transmission. Indeed, the extent of TB-induced tissue damage is closely correlated with foam cell abundance in lesions. The overarching hypothesis of this proposal is that blocking foam cell formation will facilitate macrophage-mediated clearance of M. tuberculosis infection. We recently discovered that, unlike the cholesteryl- ester-rich foam cells found in atherosclerotic lesions, foam-cell-rich and necrotic areas of tuberculous granulomas are particularly enriched in triglycerides. Given the different nature of the storage lipid, the underlying lipid accumulation mechanisms in tuberculous foam cells must differ substantially from those known to occur during atherogenesis. Thus, TB-specific interventions are needed to impede foam cell formation in TB. Infection with M. tuberculosis is associated with dysregulation of two cellular pathways involved in triglyceride homeostasis: the first, which is pro-lipogenic, includes two kinases, protein kinase B and mTOR complex 1 (Akt/mTORC1); the second, which is anti-lipogenic, includes AMP-activated protein kinase and the NAD+- dependent deacetylases called sirtuins (AMPK/SIRT). We propose a two-aim plan utilizing clinical samples from human donors and experimental infections of macrophages ex vivo and of a mouse strain producing necrotic tuberculous lung lesions (C3HeB/FeJ). These experiments will characterize: (i) the effect of anti-lipogenic treatments on antimycobacterial functions of human macrophages infected ex vivo; (ii) the relationship between activation of these pathways and control of clinical M. tuberculosis infection; and (iii) the role of anti-lipogenic treatments as adjunctive therapy for TB in C3HeB/FeJ mice. The overall objective of this proposal is to discover druggable targets in the pro-lipogenic and anti-lipogenic pathways, with the long-term goal of shortening the duration of TB treatment and improving TB-related immunopathology. This proposal is expected to lead to clinical trials of novel host-directed therapeutics against TB. More generally, these studies are expected to reveal the potential for pharmacological interventions targeting maladaptive macrophage responses in non-atherogenic diseases and to stimulate their pursuit.