Therapeutic vaccine against tuberculosis

这一探索性项目(R21)的目标是确定可用于在潜伏感染结核分枝杆菌的宿主中预防结核病(TB)的治疗性候选疫苗。我们已经开发了一种结核病的小鼠模型，在这种模型中，潜伏感染可以重复地诱导进展为疾病，而不需要对动物进行免疫操作。我们之前曾证明，一种被称为MCEL的13基因操纵子中断的结核分枝杆菌菌株无法在小鼠身上引发促炎反应，否则这种细菌就会进入肺部感染的潜伏状态。破坏操纵子假定的负调控因子mcelR会导致感染突变株的小鼠免疫反应失调。感染mcelR突变体的小鼠会出现不受控制的炎症反应--与mcel操纵子感染所观察到的反应相反。在康奈尔大学的感染模型中，mcelR突变体可以在停止使用抗生素后1个月内在小鼠身上复制致病，而不需要使用类固醇。因此，我们希望利用这个突变体 确定在停用抗生素后可防止疾病产生的结核分枝杆菌产品。 该项目的目标是1)优化小鼠康奈尔模型，以开发一种可用于小鼠治疗性疫苗试验的方案，以及2)使用为疫苗试验选择的方案识别预防结核病的结核分枝杆菌产品。我们将确定通过气雾剂途径给予的最佳接种剂量，该途径将在潜伏感染的BALB/c小鼠中重复产生疾病。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，该方案将用于筛选结核分枝杆菌产品，以防止由mcelR突变引起的这种疾病表现。然后，这些产品将作为治疗性疫苗候选。如果我们确定了这种产品，我们将寻求额外的资金，用于一个长期项目，与参与此类动物工作的人合作，在非人类灵长类动物身上评估这些产品。 针对结核病的治疗性疫苗是结核病控制的主要优先事项，我们有机会利用一种简单、廉价和可重复的动物模型，通过一种新的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.