In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice
In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice
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DOI：
10.1038/nm1683
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发表时间：
2007-12-01
期刊：
影响因子：
82.9
通讯作者：
Ehrt, Sabine
中科院分区：
文献类型：
--
作者：
Gandotra, Sheetal;Schnappinger, Dirk;Ehrt, Sabine
结核分枝杆菌（Mtb）作为一种人类病原体的成功依赖于其抵抗免疫系统根除的能力。查明使结核分枝杆菌持续存在的机制是找到限制潜伏性结核病的方法的关键。潜伏性结核病影响着世界三分之一的人口。本研究表明，条件基因沉默可用于确定体外最佳生长所需的结核分枝杆菌基因是否对毒力也很重要，如果是的话，在感染的哪个阶段需要它。将这种方法应用于编码分枝杆菌蛋白酶体核心的prcBA基因，揭示了核心蛋白酶体在小鼠慢性感染期间对Mtb持续存在的不可预测的需求。蛋白酶体耗竭也能减轻干扰素γ缺乏小鼠的Mtb，这表明蛋白酶体的功能不仅仅是防御适应性免疫反应。在体外、体内或两者中生长所必需的基因约占结核分枝杆菌基因组的20%。因此，有条件的基因沉默可以促进多达800个潜在的Mtb药物靶点的验证，并提高我们对宿主-病原体动力学的理解。
The success of Mycobacterium tuberculosis (Mtb) as a human pathogen relies on its ability to resist eradication by the immune system. The identification of mechanisms that enable Mtb to persist is key for finding ways to limit latent tuberculosis, which affects one-third of the world's population. Here we show that conditional gene silencing can be used to determine whether an Mtb gene required for optimal growth in vitro is also important for virulence and, if so, during which phase of an infection it is required. Application of this approach to the prcBA genes, which encode the core of the mycobacterial proteasome, revealed an unpredicted requirement of the core proteasome for the persistence of Mtb during the chronic phase of infection in mice. Proteasome depletion also attenuated Mtb in interferon gamma-deficient mice, pointing to a function of the proteasome beyond defense against the adaptive immune response. Genes that are essential for growth in vitro, in vivo or both account for approximately 20% of Mtb's genome. Conditional gene silencing could therefore facilitate the validation of up to 800 potential Mtb drug targets and improve our understanding of host-pathogen dynamics.