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(申请人提供)：目前的结核病化疗不能100%迅速消除结核分枝杆菌。虽然99%的细菌在开始治疗后的三周内被消除，但一小部分耐药杆菌(~1%)需要额外的6-8个月的多药治疗才能消除。 这种治疗方案在早期显著改善了患者的健康状况，因此许多患者未能完成完整的长期治疗。这一限制促进了已在全球传播的耐多药(MDR)和广泛耐药(XDR)结核分枝杆菌菌株的不断出现。这项提议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，通过使用免疫疗法来对抗肺部免疫抑制，有可能增强宿主自身的杀菌反应。我们的初步研究表明，针对转化生长因子1细胞因子的小干扰RNA[siRNA]转录本的交付减少了慢性感染结核分枝杆菌的小鼠的肺部细菌负荷。此外，在没有IL-10细胞因子的情况下，这种作用会增强。在这里，我们将测试靶向转化生长因子1和IL-10的siRNA是否可以增强耐药杆菌的清除，以及这种方法是否对慢性耐多药结核病感染有效。结果将使用现在我们实验室常规的综合细菌学、免疫学和病理学方法进行记录。我们独一无二地配备了最先进的BSL-III研究设施，并组建了一支经验丰富的研究团队，他们拥有分支杆菌感染和真核细胞RNA调控领域的专业知识。因此，该应用程序使用创新的尖端研究来开发针对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