Therapeutic vaccine against tuberculosis

该探索性项目（R21）的目标是确定可用于预防结核分枝杆菌潜伏感染宿主中结核病（TB）的治疗性候选疫苗。我们已经开发了一种小鼠结核病模型，其中潜伏感染可以被可重复地诱导发展为疾病，而无需对动物进行免疫操作。我们以前的研究表明，一株M.被称为mcel的13基因操纵子破坏的结核病不能在小鼠中引发促炎反应，否则会使生物体进入肺部感染的潜伏状态。操纵子的假定负调节因子（称为mcelR）的破坏导致感染突变株的小鼠的免疫反应失调。感染mcelR突变体的小鼠产生了不受控制的炎症反应-与mcel操纵子感染观察到的反应相反。在康奈尔感染模型中，mcelR突变体可以在停止抗生素后1个月内在小鼠中可重复地引起疾病，而无需施用类固醇。因此，我们希望利用这种突变体， 识别M。结核病产品，将防止疾病的生产后，停止抗生素。 该项目的目的是1）优化小鼠康奈尔模型，以开发可用于小鼠治疗性疫苗试验的方案，以及2）鉴定M。使用选定的疫苗试验方案预防结核病的结核病产品。我们将确定通过气雾剂途径给药的最佳接种剂量，该剂量将在潜伏感染的BALB/c小鼠中可重复地产生疾病。我们还将确定疾病在一段潜伏期后出现的最佳时间段。一旦建立了这些条件，本方案将用于筛选M。结核病的产品，将防止这种疾病的表现所造成的mcelR突变。这些产品将作为治疗性候选疫苗。如果我们确实发现了这些产品，我们将寻求额外的资金，用于一个长期项目，与那些参与此类动物工作的人合作，在非人类灵长类动物中评估这些产品。 针对结核病的治疗性疫苗是结核病控制的主要优先事项，我们有机会通过使用简单、廉价和可重复的动物模型的新方法来鉴定此类产品。

The goal of this exploratory project (R21) is to identify therapeutic vaccine candidates that can be used to prevent tuberculosis (TB) in hosts latently infected with Mycobacterium tuberculosis. We have developed a mouse model of TB in which latent infection can be reproducibly induced to progress to disease without immunologically manipulating the animal. We previously showed that a strain of M. tuberculosis disrupted in a 13-gene operon called mcel is unable to elicit a pro-inflammatory response in mice that would otherwise allow the organism to enter a latent state of infection in the lungs. Disruption of the operon's putative negative regulator called mcelR leads to dysregulation of the immune response in mice infected with the mutant strain. The mouse infected with the mcelR mutant mounts an uncontrolled inflammatory response--opposite of the response observed with the mcel operon infection. In the Cornell model of infection, the mcelR mutant can reproducibly cause disease in mice within 1 month after cessation of antibiotics, without the administration of steroids. We wish to, therefore, use this mutant to identify M. tuberculosis products that will prevent disease production following cessation of antibiotics. The aims of the project are to 1) optimize the mouse Cornell model to develop a protocol that can be used for a therapeutic vaccine trial in mice, and 2) identify M. tuberculosis products that prevent TB using the selected protocol for the vaccine trial. We will identify the optimal inoculum dose administered by an aerosol route that will reproducibly produce disease in latently infected BALB/c mice. We will also identify the optimal time period in which disease manifests after a period of latency. Once these conditions are established, this protocol will be used to screen M. tuberculosis products that will prevent this disease manifestation caused by the mcelR mutant. Such products will then serve as therapeutic vaccine candidates. If we do identify such products, we will seek additional funding for a long-term project to evaluate such products in nonhuman primates in collaboration with those involved in such animal work. Therapeutic vaccines against TB is a major priority in TB control, and we have an opportunity to identify such products by a novel approach using a simple, inexpensive, and reproducible animal model.