Molecular Pathogenesis Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
Front Cell Infect Microbiol. 2017 Oct 10;7:439. doi: 10.3389/fcimb.2017.00439. eCollection 2017.
( infection manifests into tuberculosis (TB) in a small fraction of the infected population that comprises the TB susceptible group. Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression. The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses. While high cholesterol levels are clinically proven condition for perturbations in cardiac health, a significant fraction of population these days suffer from borderline risk cholesterol profiles. This apparently healthy population is susceptible to various health risks placing them in the "pre-disease" range. Our study focuses on determining the role of such asymptomatic dyslipidemia as a potential risk factor for susceptibility to TB persistence. Macrophages exposed to sub-pathological levels of cholesterol for chronic period, besides impaired release of TNF-α, could not clear intracellular pathogenic mycobacteria effectively as compared to the unexposed cells. These cells also allowed persistence of opportunistic mycobacterial infection by and BCG, indicating highly compromised immune response. The cholesterol-treated macrophages developed a foamy phenotype with a significant increase in intracellular lipid-bodies prior to infection, potentially contributing to pre-disease state for tuberculosis infection. The foamy phenotype, known to support infection, increased several fold upon infection in these cells. Additionally, mitochondrial morphology and function were perturbed, more so during infection in cholesterol treated cells. Pharmacological supplementation with small molecule M1 that restored mitochondrial structural and functional integrity limited survival more effectively in cholesterol exposed macrophages. Mechanistically, M1 molecule promoted clearance of mycobacteria by reducing total cellular lipid content and restoring mitochondrial morphology and function to its steady state. We further supported our observations by infection assays in PBMC-derived macrophages from clinically healthy volunteers with borderline risk cholesterol profiles. With these observations, we propose that prolonged exposure to sub-pathological cholesterol can lead to asymptomatic susceptibility to persistence. Use of small molecules like M1 sets yet another strategy for host-directed therapy where re-functioning of mitochondria in cholesterol abused macrophages can improve clearance.
（在一小部分易感染人群中，感染会发展为结核病（TB），这些人构成了结核病易感人群。确定促进结核病持续存在的易感性的因素是结核病控制计划的主要议程之一。最近，世界卫生组织将糖尿病确认为结核病疾病进展的一个危险因素。代谢失衡的密切相关病理状态，血脂异常，是另一个涉及宿主免疫反应失调的新兴危险因素。虽然高胆固醇水平是心脏病健康受损的临床公认条件，但如今相当一部分人群的胆固醇水平处于边缘风险。这些看似健康的人群容易受到各种健康风险的影响，使他们处于“疾病前期”范围。我们的研究重点是确定这种无症状血脂异常作为易感性结核病持续存在的潜在危险因素的作用。暴露于亚病理水平胆固醇的巨噬细胞除了 TNF-α释放受损外，与未暴露的细胞相比，无法有效清除细胞内的致病性分枝杆菌。这些细胞还允许机会性分枝杆菌感染和 BCG 的持续存在，表明免疫反应严重受损。与未处理的细胞相比，用胆固醇处理的巨噬细胞在 感染前会发展出泡沫样表型，细胞内脂滴显著增加，这可能导致结核病感染的疾病前期状态。这种泡沫样表型已知支持 感染，在这些细胞感染后会增加几倍。此外，胆固醇处理的细胞中线粒体形态和功能受到干扰，在感染过程中更为严重。用小分子 M1 进行药理学补充，恢复了线粒体的结构和功能完整性，从而更有效地限制了胆固醇暴露的巨噬细胞中的 存活。从机制上讲，M1 分子通过降低总细胞脂质含量并将线粒体形态和功能恢复到稳定状态来促进分枝杆菌的清除。我们进一步通过对来自具有边缘风险胆固醇水平的临床健康志愿者的 PBMC 衍生巨噬细胞进行感染实验来支持我们的观察结果。有了这些观察结果，我们提出，长期暴露于亚病理水平的胆固醇会导致无症状的 持续存在易感性。使用小分子如 M1 为宿主定向治疗提供了另一种策略，在胆固醇滥用的巨噬细胞中重新发挥线粒体的功能可以提高 的清除率。
