Statins as Adjunctive, Host-Directed Therapy for TB

 描述（由申请人提供）：已知结核分枝杆菌（Mtb）可破坏免疫反应，从而建立感染并引起疾病。因此，宿主导向治疗（HDT）作为传统抗结核治疗方案的替代治疗，是一种有吸引力的策略。在这项提案中，我们将研究新的假设，他汀类药物（HMG-CoA还原酶抑制剂）可以作为预防性HDT，允许治疗药物敏感的结核病缩短和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。脂质在携带结核分枝杆菌的巨噬细胞中的积累与一线药物的持久性和表型耐受性相关，这反过来又导致治疗持续时间延长。我们和其他人已经表明，他汀类药物，虽然缺乏直接的抗菌作用，减少结核分枝杆菌的生长和感染诱导的脂质积累在巨噬细胞，并促进吞噬体成熟和自噬。我们还证明了在标准的慢性肺结核小鼠模型中，辛伐他汀的连续治疗增强了一线抗肺结核方案的杀菌活性 减少感染，缩短治愈时间。此外，他汀类药物已被证明可以减少小鼠模型中TB诱导的肺部病理学。在本申请中，我们提出了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抑制-反应关系，并确定最有希望的化合物和剂量进行临床测试。在选择了“主导”他汀类药物后，我们将进行一项两阶段的概念验证临床试验，其中将通过现有的NIH和南非MRC支持的临床研究中心（位于南非索韦托和Matlosana）招募药物敏感的肺结核患者（伴或不伴HIV合并感染）。第1阶段的受试者将随机接受一线抗结核治疗方案（含或不含两种不同剂量的他汀类药物），以评价安全性、PK和药物相互作用，并选择第2阶段的他汀类药物剂量。在第2阶段，我们将确定他汀类药物与一线结核病治疗联合使用时缩短痰培养转阴所需时间以及其他次要临床、放射学、微生物学和实验室结局的能力。在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暴露，以阐明他汀类药物对巨噬细胞的已知抗TB机制的影响，包括感染诱导的脂质积聚、吞噬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III期研究。我们的提案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卓越中心和罗格斯新泽西医学院的多学科研究团队之间的持续合作。我们的研究结果有可能大大提高我们对宿主-生物体相互作用的理解，并在临床上验证他汀类药物作为一种预防性HDT，可以缩短TB治疗的持续时间并改善肺功能相关的结果。

 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.