Host targeted immunotherapy for TB treatment

描述（由申请人提供）：目前的结核病化疗不能迅速消除百分之百的结核分枝杆菌。虽然99%的细菌在开始治疗的三周内被消除，但一小部分（约1%）耐药杆菌需要额外的6-8个月的多药治疗才能消除。 这种治疗方案导致患者健康在早期得到显著改善，因此许多患者未能完成完整的长期治疗。这种局限性促进了多药耐药（MDR）和广泛耐药（XDR）结核分枝杆菌菌株的持续出现，并在全球范围内传播。该提案的主要目标是使用免疫方法更快地根除耐药杆菌。我们相信通过免疫疗法对抗肺部免疫抑制，可以增强宿主自身的杀菌反应。我们的初步研究表明，靶向TGF？1细胞因子的小干扰RNA（siRNA）转录物的递送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，这种作用在不存在IL-10细胞因子的情况下增强。在这里，我们将测试靶向TGF β 1和IL-10的siRNA是否可以增强耐药杆菌的清除，以及这种方法在慢性MDR-TB感染中是否有效。结果将记录使用全面的细菌学，免疫学，病理学的方法，现在常规在我们的实验室。我们独特地配备了最先进的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。因此，本申请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。

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.