Ashley David, Hernandez Joshua, Cao Ruoqiong, To Kimberly, Yegiazaryan Aram, Abrahem Rachel, Nguyen Timothy, Owens James, Lambros Maria, Subbian Selvakumar, Venketaraman Vishwanath
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
J Clin Med. 2020 Jun 29;9(7):2043. doi: 10.3390/jcm9072043.
has been historically and is currently a threat to global public health. First-line antibiotics have been effective but proven to be burdensome as they have many potential adverse side effects. There has been a recent increase in the number of active tuberculosis (TB) cases due to a prevalence of multidrug and extensively drug-resistant strains of , and an increasing number of highly susceptible people such as those with Type 2 Diabetes (T2DM) and human immunodeficiency virus (HIV) infection. Multidrug-resistant infection (MDR-TB) is challenging to treat with existing therapeutics, so novel therapeutics and treatment strategies must be developed. Host-Directed Therapy (HDT) has been a potential target mechanism for effective clearance of infection. Host cell autophagy plays an essential role in antibacterial defense. The mammalian target of rapamycin (mTOR) has been negatively correlated with autophagy induction. Everolimus is an mTOR inhibitor that induces autophagy, but with higher water solubility. Therefore, targeting the mTOR pathway has the potential to develop novel and more effective combination drug therapy for TB. This study tested the effect of everolimus, alone and in combination with current first-line antibiotics (isoniazid and pyrazinamide), on the inhibition of inside in vitro human granulomas. We found that -infected in vitro granulomas treated with everolimus alone resulted in significantly decreased burden compared to similar granulomas in the control group. Cells treated with everolimus doses of either 1 nM or 2 nM in conjunction with pyrazinamide (PZA) produced a significant reduction in intracellular burden. Treatment groups that received everolimus alone in either 1 nM or 2 nM doses experienced a significant reduction in oxidative stress. Additionally, samples treated with 2 nM everolimus alone were observed to have significantly higher levels of autophagy and mTOR inhibition as well. Results from this study indicate that everolimus is efficacious in controlling infection in the granulomas and has additive effects when combined with the anti-TB drugs, isoniazid and pyrazinamide. This study has shown that everolimus is a promising host-directed therapeutic in the context of in vitro granuloma infection. Further study is warranted to better characterize these effects.
从历史上看，它一直且目前仍是对全球公共卫生的一种威胁。一线抗生素曾经有效，但事实证明其负担较重，因为它们有许多潜在的不良副作用。由于多重耐药和广泛耐药菌株的流行，以及越来越多的高易感人群，如2型糖尿病（T2DM）患者和人类免疫缺陷病毒（HIV）感染者，近期活动性肺结核（TB）病例数有所增加。多重耐药结核感染（MDR-TB）用现有疗法治疗具有挑战性，因此必须开发新的疗法和治疗策略。宿主导向疗法（HDT）一直是有效清除感染的潜在靶标机制。宿主细胞自噬在抗菌防御中起重要作用。雷帕霉素靶蛋白（mTOR）与自噬诱导呈负相关。依维莫司是一种诱导自噬但水溶性更高的mTOR抑制剂。因此，靶向mTOR途径有可能开发出用于治疗结核病的新型且更有效的联合药物疗法。本研究测试了依维莫司单独使用以及与当前一线抗生素（异烟肼和吡嗪酰胺）联合使用对体外人肉芽肿内结核分枝杆菌抑制的效果。我们发现，与对照组的类似肉芽肿相比，单独用依维莫司处理的体外感染结核分枝杆菌的肉芽肿导致结核分枝杆菌负担显著降低。用1 nM或2 nM依维莫司剂量联合吡嗪酰胺（PZA）处理的细胞使细胞内结核分枝杆菌负担显著降低。单独接受1 nM或2 nM依维莫司剂量治疗的组氧化应激显著降低。此外，观察到单独用2 nM依维莫司处理的样本自噬水平和mTOR抑制水平也显著更高。本研究结果表明，依维莫司在控制肉芽肿内结核分枝杆菌感染方面有效，并且与抗结核药物异烟肼和吡嗪酰胺联合使用时有相加作用。本研究表明，在体外肉芽肿结核分枝杆菌感染的背景下，依维莫司是一种有前景的宿主导向疗法。有必要进行进一步研究以更好地表征这些作用。
