Host targeted immunotherapy for TB treatment

结核病治疗的宿主靶向免疫疗法

• 批准号: 8487363
• 负责人: Mercedes Gonzalez-Juarrero
• 金额: $ 19.22万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487363
• 关键词: Adjuvant; Animal Model; Anti-Bacterial Agents; Antitubercular Agents; Attention; Bacillus (bacterium); Bacteria; Categories; Chronic; Containment; Country; Data; Development; Drug Targeting; Environment; Equilibrium; Eukaryotic Cell; Extreme drug resistant tuberculosis; France; Goals; Health; Immune; Immune Targeting; Immune response; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Interleukin-10; Intervention; Laboratories; Lung; Mediating; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population; Production; RNA; Regulation; Reporting; Research; Research Personnel; Role; Small Interfering RNA; Staging; Testing; Therapeutic; Therapeutic Agents; Transcript; Treatment Protocols; Tuberculosis; Vaccines; Validation; Wild Type Mouse; alternative treatment; arm; bactericide; base; chemotherapy; combat; cytokine; design; drug clearance; drug discovery; effective therapy; experience; gene therapy; global health; improved; in vivo; innovation; meetings; non-compliance; novel; pathogen; public health relevance; research facility; response; therapeutic target; treatment strategy; tuberculosis treatment

DESCRIPTION (provided by applicant): Current TB chemotherapy is incapable of rapidly eliminating one hundred percent of the Mycobacterium tuberculosis bacilli. Although 99% of the bacteria are eliminated within three weeks of commencing treatment, a small population (~ 1%) of drug-tolerant bacilli requires an additional 6-8 months of multidrug treatment to be eliminated. This treatment regimen results in a dramatic improvement in patient health early on and many patients therefore fail to complete the full long-term treatment. This limitation has facilitated te continued emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains which have spread globally. The primary goal of this proposal is to more rapidly eradicate drug tolerant bacilli using immunotherapeutic approaches. We believe it is possible to enhance the host's own bactericidal response by using immunotherapy to combat pulmonary immunosuppression. Our preliminary studies indicate that delivery of small interfering RNA [siRNA] transcripts targeting the TGF¿1 cytokine reduces the pulmonary bacterial load of mice chronically infected with Mycobacterium tuberculosis. Moreover, this effect is enhanced in the absence of the IL-10 cytokine. Here we will test whether siRNA targeting of TGF¿1 and IL-10 can enhance clearance of drug tolerant bacilli and whether this approach is efficacious in chronic MDR-TB infections. The outcomes will be documented using comprehensive bacteriologic, immunologic, pathologic approaches now routine in our laboratory. We are uniquely equipped with state-of-the-art BSL-III research facilities and have assembled a team of highly experienced researchers with expertise in the fields of mycobacteria infection and RNA regulation in eukaryotic cells. Thus, this application uses innovative, cutting- edge research to develop anti-bacterial products directed against NIAID Category C Priority Pathogens.

描述（由申请人提供）：目前的结核病化疗无法快速消除 100% 的结核杆菌，尽管 99% 的细菌在开始治疗后三周内被消除，但仍有一小部分（约 1%）的细菌。耐药杆菌需要额外 6-8 个月的多药治疗才能消除。 这种治疗方案使患者早期健康状况得到显着改善，因此许多患者无法完成完整的长期治疗，这种限制促进了多重耐药（MDR）和普遍耐药（XDR）分枝杆菌的持续出现。该提案的主要目标是使用免疫治疗方法更快地根除耐药杆菌。我们相信通过使用免疫治疗方法可以增强宿主自身的杀菌反应。我们的初步研究表明，针对 TGF 的小干扰 RNA [siRNA] 转录本的递送。 1 细胞因子可减少慢性感染结核分枝杆菌的小鼠的肺部细菌负荷，而且，在没有 IL-10 细胞因子的情况下，这种作用会增强。在这里，我们将测试 siRNA 是否靶向 TGF¿ 1 和 IL-10 可以增强耐药杆菌的清除，并且这种方法对慢性耐多药结核感染是否有效，将使用我们实验室目前常规的综合细菌学、免疫学、病理学方法来记录结果。 - 最先进的 BSL-III 研究设施，并组建了一支经验丰富的研究人员团队，他们在分枝杆菌感染和真核细胞 RNA 调控领域具有专业知识。前沿研究开发针对 NIAID C 类优先病原体的抗菌产品。

项目成果

Host Directed Therapy for Chronic Tuberculosis via Intrapulmonary Delivery of Aerosolized Peptide Inhibitors Targeting the IL-10-STAT3 Pathway.

• DOI: 10.1038/s41598-018-35023-0
• 发表时间: 2018-11-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Upadhyay R;Sanchez-Hidalgo A;Wilusz CJ;Lenaerts AJ;Arab J;Yeh J;Stefanisko K;Tarasova NI;Gonzalez-Juarrero M
• 通讯作者: Gonzalez-Juarrero M