Antimicrobial Discovery Center and Department of Biology, Northeastern University, Boston, Massachusetts, USA.
mBio. 2011 Jun 14;2(3):e00100-11. doi: 10.1128/mBio.00100-11. Print 2011.
Tuberculosis continues to be a major public health problem in many parts of the world. Significant obstacles in controlling the epidemic are the length of treatment and the large reservoir of latently infected people. Bacteria form dormant, drug-tolerant persister cells, which may be responsible for the difficulty in treating both acute and latent infections. We find that in Mycobacterium tuberculosis, low numbers of drug-tolerant persisters are present in lag and early exponential phases, increasing sharply at late exponential and stationary phases to make up ~1% of the population. This suggests that persister formation is governed by both stochastic and deterministic mechanisms. In order to isolate persisters, an exponentially growing population was treated with d-cycloserine, and cells surviving lysis were collected by centrifugation. A transcriptome of persisters was obtained by using hybridization to an Affymetrix array. The transcriptome shows downregulation of metabolic and biosynthetic pathways, consistent with a certain degree of dormancy. A set of genes was upregulated in persisters, and these are likely involved in persister formation and maintenance. A comparison of the persister transcriptome with transcriptomes obtained for several in vitro dormancy models identified a small number of genes upregulated in all cases, which may represent a core dormancy response.
结核病在世界许多地区仍然是一个主要的公共卫生问题。控制这一流行病的主要障碍是治疗时间长和潜伏感染人数众多。细菌形成休眠、耐药的持久生存细胞，这可能是治疗急性和潜伏感染困难的原因。我们发现，在结核分枝杆菌中，处于潜伏期和早期指数期的耐药持久生存细胞数量较少，在晚期指数期和静止期急剧增加，占种群的~1%。这表明持久生存的形成受随机和确定性机制的控制。为了分离持久生存细胞，用 d-环丝氨酸处理指数生长的细菌种群，然后通过离心收集裂解后存活的细胞。通过与 Affymetrix 微阵列杂交获得了持久生存细胞的转录组。转录组显示代谢和生物合成途径的下调，与一定程度的休眠一致。一组基因在持久生存细胞中上调，这些基因可能参与持久生存的形成和维持。将持久生存的转录组与几种体外休眠模型的转录组进行比较，发现所有情况下都有少数基因上调，这可能代表一个核心休眠反应。
