Statins as Adjunctive, Host-Directed Therapy for TB

 描述(由申请人提供)：结核分枝杆菌(结核分枝杆菌)是已知的颠覆免疫反应，以建立感染和导致疾病。因此，宿主导向治疗(HDT)作为传统抗结核方案的辅助治疗，是一种有吸引力的策略。在这项提案中，我们将研究他汀类药物(HMG-CoA还原酶抑制剂)可以作为辅助HDT的新假设，从而缩短对药物敏感的结核病的治疗时间，并改善肺部炎症和功能。在最常用的处方药中，他汀类药物具有降脂和免疫调节特性。携带结核分枝杆菌的巨噬细胞中脂质的积累与一线药物的持久性和表型耐受性有关，这反过来又导致治疗持续时间的延长。我们和其他人已经证明，他汀类药物虽然缺乏直接的抗菌作用，但可以减少结核分枝杆菌的生长和感染诱导的巨噬细胞中的脂质堆积，并促进吞噬体成熟和自噬。我们还证明了辛伐他汀辅助治疗增强了一线抗结核方案在标准的慢性结核病小鼠模型中的杀菌活性。 并减少治愈所需的时间。此外，他汀类药物已被证明可以减少结核病诱导的小鼠模型的肺部病理。在这一应用中，我们建议在巨噬细胞和临床相关的小鼠模型中进行临床前研究，这将使我们能够比较各种他汀类药物的活性和暴露-反应关系，并确定最有希望的化合物和剂量进行临床测试。在选择“主导”他汀类药物后，我们将进行一项分两个阶段的概念验证临床试验，通过位于南非索韦托和马特洛萨纳的NIH和南非MRC支持的现有临床站点招募对药物敏感的肺结核病患者(合并或不合并艾滋病毒感染)。第一阶段的参与者将随机接受一线抗结核方案，包括或不包括两种不同剂量的他汀铅，以评估安全性、PK和药物相互作用，并选择第二阶段的他汀类药物剂量。在第二阶段，我们将确定他汀类药物与一线结核病治疗结合使用时，缩短痰培养转为阴性所需时间的能力，以及其他次要的临床、放射学、微生物学和实验室结果。临床试验中测量的他汀类药物的血浆浓度以及已发表的数据将用于指导他汀类药物的暴露，以阐明他汀类药物对巨噬细胞已知的抗结核病机制的影响，包括感染诱导的脂质堆积、吞噬小体成熟和自噬以及促炎细胞因子的分泌。这些知识将有助于设计未来的第三阶段研究。我们的建议利用了约翰霍普金斯大学医学院、威特沃特斯兰德大学DST/NRF卓越中心和新泽西罗格斯医学院的多学科研究团队之间的持续合作。我们的发现有可能极大地提高我们对宿主-机体相互作用的理解，并在临床上验证他汀类药物作为一种辅助HDT可以缩短结核病治疗时间并改善肺功能相关结果。

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) is known to subvert immune responses to establish infection and cause disease. Thus, host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. In this proposal, we will investigate the novel hypothesis that statins (HMG-CoA reductase inhibitors) can serve as adjunctive HDT, permitting treatment shortening for drug-susceptible TB and improving lung inflammation and function. Among the most commonly prescribed drugs, statins have lipid-lowering and immunomodulatory properties. Accumulation of lipids in macrophages harboring Mtb has been associated with persistence and phenotypic tolerance to front-line drugs, which leads, in turn, to prolonged treatment duration. We and others have shown that statins, while lacking a direct antimicrobial effect, reduce Mtb growth and infection-induced lipid accumulation in macrophages, and promote phagosomal maturation and autophagy. We also have demonstrated that adjunctive therapy with simvastatin enhances the bactericidal activity of the first-line anti-TB regimen in a standard mouse model of chronic TB infection and reduces the time required for cure. Furthermore, statins have been shown to reduce TB-induced lung pathology in the mouse model. In this application, we propose preclinical studies in macrophages and in a clinically relevant murine model that will allow us to compare activity and exposure-response relationships of various statins and to identify the most promising compound and doses to test clinically. Upon selection of the "lead" statin, we will conduct a two-stage, proof-of-concept clinical trial, in which patients with drug-susceptible, pulmonary TB (with or without HIV co-infection) will be recruited through existing NIH- and South African MRC-supported clinical sites in Soweto and Matlosana, South Africa. Participants in Stage 1 will be randomized to receive the first-line antitubercular regimen with or without the lead statin provided at two different doses for evaluation of safety, PK, and drug interactions, and for selecting the statin dose for Stage 2. In Stage 2, we will determine the ability of the statin, when given in combination with first-line TB treatment, to shorten the time required for sputum culture conversion to negative, as well as other secondary clinical, radiological, microbiological, and laboratory-based outcomes. The plasma concentrations of statin measured in the clinical trial, as well as published data, will be used to guide statin exposures to elucidae the statin's effects on known anti-TB mechanisms of macrophages, including infection-induced lipid accumulation, phagosome maturation and autophagy, and secretion of pro-inflammatory cytokines. This knowledge will help design future Phase III studies. Our proposal leverages an ongoing collaboration between multidisciplinary teams of investigators at Johns Hopkins University School of Medicine, University of the Witwatersrand DST/NRF Centre of Excellence, and Rutgers New Jersey Medical School. Our findings have the potential to substantially advance our understanding of host-organism interactions and clinically validate statins as an adjunctive HDT that can shorten the duration of TB treatment and improve lung function-related outcomes.