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

基于纳米颗粒的宿主定向疗法根除结核分枝杆菌

• 批准号: 10613424
• 负责人: Admire Dube
• 金额: $ 31.82万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613424
• 关键词: Address; Adherence; Advanced Development; Alveolar Macrophages; Animal Model; Antibacterial Response; Antibiotics; Antimicrobial Effect; Appearance; Architecture; Artificial nanoparticles; Award; Bacteria; Bacterial Infections; Biocompatible Materials; Biomimetics; Bone Marrow; Case Study; Cause of Death; Cells; Cessation of life; Clinical; Communicable Diseases; Country; Data; Defense Mechanisms; Development; Disadvantaged; Disease; Drug Tolerance; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Exhibits; Fluorescence; Formulation; Funding; Goals; HIV; Health; Human; Hybrids; Immune; Immune response; Immunity; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Infection; Institution; Invaded; Kinetics; Knowledge; Lipids; Macrophage; Macrophage Activation; Mediating; Metals; Methods; Modeling; Molecular; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; Mycolic Acid; Nanotechnology; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Polymers; Polysaccharides; Population; Positioning Attribute; Property; Public Health; Publishing; Regimen; Reporter; Research; Research Personnel; Research Project Grants; Research Training; Rod; Scientist; Shapes; Signal Transduction; South Africa; South Dakota; Standardization; Structure; System; Training Programs; Treatment Failure; Treatment Protocols; Tuberculosis; United States; United States National Institutes of Health; Universities; Virulent; Work; Zimbabwe; antimicrobial; beta-Glucans; co-infection; drug-sensitive; immunoregulation; improved; in vivo; innovation; latent infection; mimicry; multidisciplinary; mycobacterial; nanomedicine; nanoparticle; nanopolymer; novel; novel therapeutic intervention; pathogen; persistent bacteria; polycaprolactone; resistant strain; response; tool; trafficking; tuberculosis treatment; uptake

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.

摘要 结核病仍然是一个主要的全球公共卫生威胁。尽管相对有效的药物方案是 治疗失败仍然是结核病控制的主要障碍。这部分是由于 耐药结核分枝杆菌(Mtb)菌株的发病率以及细菌现象 坚持不懈。持久者代表潜伏感染的蓄水池，当宿主感染时，潜伏感染可能进展为活动性疾病。 免疫力受到损害(例如，与艾滋病毒合并感染)，也可能导致出现进一步的 抗药性。MTB能够颠覆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，并在这种宿主内创建一个受保护的利基 手机。在这项拟议的工作中，工程纳米颗粒能够有利地调节 巨噬细胞通过传递免疫调节信号，实现细胞内结核分枝杆菌的死亡， 调查过了。这些独特的纳米颗粒在大小、形状和特定方面模仿结核分枝杆菌(即细菌仿制)。 组成。本文提出的纳米粒子有脂质聚合物杂化纳米粒子和金属有机纳米粒子。 含有真菌酸和/或真菌壁多糖β-的框架(球形和杆状) 葡聚糖。已发表的和初步的强有力的数据表明，聚合物纳米颗粒具有诱导 杀死巨噬细胞中的毒力结核分枝杆菌。这种杀灭只在细胞内的结核分枝杆菌中才明显，并且与所实现的类似 使用抗生素。金属有机骨架纳米粒子可被巨噬细胞包覆 目标材料。该项目的假设是，模拟细菌的免疫治疗纳米颗粒将 通过免疫有效地对抗所有形式的结核分枝杆菌(包括耐药和持续感染的人群) 调制。具体地说，该项目有3个目标：1)表征一组仿菌免疫疗法 NPS；2)调查感染的巨噬细胞和细胞内细菌对NPs小组的反应；3)评估 NPs在小鼠感染模型中的体内反应和疗效。这个项目处于最前沿的 纳米技术和结核病研究，并将提供几个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 艾滋病毒研究培训计划)。跨国研究小组将由3名新的调查人员领导，其中 来自南非斯泰伦博什大学、西开普省大学(历史上 南非贫困机构)和美国南达科他州立大学合作提出了一项 基于纳米微粒递送系统的结核病免疫治疗新方法。这支队伍有 在纳米颗粒配方和特性、体外和体内感染模型以及结核病方面的专业知识 免疫学。我们的结果将推动基于纳米颗粒的、宿主导向的治疗方法的发展 肺结核。