Nanoparticle-based host-directed therapies for eradication of Mycobacterium tuberculosis

总结 结核病仍然是一个重大的全球公共卫生威胁。虽然相对有效的药物治疗方案， 尽管现有的结核病治疗方法有限，但治疗失败仍然是结核病控制的主要障碍。这部分是由于高 耐药结核分枝杆菌（Mtb）菌株的发病率，以及细菌感染的现象， 持久性。持续感染是潜伏感染的一个储存库，当宿主 免疫性受到损害（例如，与艾滋病毒合并感染），也可能有助于出现进一步的 耐药性结核分枝杆菌能够破坏宿主巨噬细胞发挥的关键先天免疫防御机制; 它可以抑制免疫反应，破坏巨噬细胞的杀伤，并在宿主体内创造一个受保护的小生境， cell.在拟议的工作中，工程纳米粒子的能力，以有利地调节的反应， 巨噬细胞，通过传递免疫调节信号，并实现细胞内结核分枝杆菌的死亡，将是 研究了这些独特的纳米颗粒在尺寸、形状和尺寸的选定方面模拟Mtb（即拟细菌）。 混合物.这里提出的纳米粒子是脂质聚合物杂化纳米粒子和金属有机物纳米粒子。 掺入分枝菌酸和/或真菌壁多糖β- 葡聚糖。强有力的已发表和初步数据表明，聚合物纳米颗粒诱导 杀死巨噬细胞中的毒性Mtb。这种杀伤仅在细胞内Mtb中明显，并且与所实现的类似。 使用抗生素。可以合成金属有机骨架纳米颗粒并包裹巨噬细胞 目标材料。该项目的假设是，拟细菌，免疫纳米粒子将 通过免疫接种有效对抗所有形式的结核分枝杆菌（包括耐药和持续存在的人群） 调变具体而言，该项目有3个目标：1）表征一组拟细菌免疫酶 NP; 2）研究感染的巨噬细胞和细胞内细菌对NP组的响应; 3）评估 在鼠感染模型中对NP的体内应答和功效。这个项目是在尖端的 纳米技术和结核病研究，并将提供几项令人兴奋的研究能力发展 为来自南非和津巴布韦的科学家提供机会（通过与正在进行的NIH资助的 艾滋病毒研究培训方案）。多国研究团队将由3名新研究人员领导， 来自南非斯泰伦博斯大学、西开普大学（一个历史上 南非的弱势机构）和美国的南达科他州州立大学合作，提出了一项 基于纳米颗粒的递送系统的结核病免疫治疗新方法。该团队已经 纳米颗粒制剂和表征、体外和体内感染模型以及结核病方面的专业知识 免疫学我们的研究结果将推动基于纳米颗粒的宿主导向疗法的发展， 结核

SUMMARY Tuberculosis remains a major global public health threat. Although relatively effective drug regimens are available, treatment failure remains a major roadblock to tuberculosis control. This is in part due to a high incidence of drug-resistant Mycobacterium tuberculosis (Mtb) strains, as well as the phenomenon of bacterial persistence. Persisters represent a reservoir of latent infection, which may progress to active disease when host immunity is compromised (e.g., with HIV co-infection), and also potentially contribute to the emergence of further drug resistance. Mtb is able to subvert key innate immune defence mechanisms exerted by the host macrophage; it can dampen the immune response, subvert macrophage killing and create a protected niche within this host cell. In the proposed work, the capacity of engineered nanoparticles to favourably modulate the response of macrophage, through delivered immunomodulatory signals, and achieve death of intracellular Mtb, will be investigated. These unique nanoparticles mimic Mtb (i.e. bacteriomimetic) in selected aspects of size, shape and composition. The nanoparticles proposed here are lipid polymer hybrid nanoparticles and metal organic frameworks (spherical and rod shaped) incorporating mycolic acids and/or the fungal wall polysaccharide β- glucan. Strong published and preliminary data demonstrates the capacity of the polymer nanoparticles to induce killing of virulent Mtb in macrophages. This killing is only evident in intracellular Mtb and is similar to that achieved using an antibiotic. Metal organic framework nanoparticles can be synthesized and coated with macrophage targeting materials. The hypothesis of the project is that bacteriomimetic, immunotherapeutic nanoparticles will be effective against all forms of Mtb (including drug-resistant and persister populations) through immune modulation. Specifically, the project has 3 aims: 1) Characterize a panel of bacteriomimetic immunotherapeutic NPs; 2) Investigate response of infected macrophages and intracellular bacteria to the panel of NPs; 3) Assess in vivo response to, and efficacy of, NPs in murine infection model. This project is at the cutting edge of nanotechnology and tuberculosis research, and will provide several exciting research capacity development opportunities for scientists from South Africa and Zimbabwe (through a partnership with an on-going NIH funded HIV Research Training Program). The multi-national research team will be led by 3 new investigators, with research teams from Stellenbosch University, South Africa, the University of the Western Cape (a historically disadvantaged institution in South Africa) and South Dakota State University in the USA, partnered to propose a novel immunotherapy approach for tuberculosis based on nanoparticle-based delivery systems. The team has expertise in nanoparticle formulation and characterisation, in vitro and in vivo infection models, and tuberculosis immunology. Our results will advance the development of nanoparticle-based, host-directed therapies for tuberculosis.