Hypoxia Sensing and Persistence Genes Are Expressed during the Intragranulomatous Survival of Mycobacterium tuberculosis
Hypoxia Sensing and Persistence Genes Are Expressed during the Intragranulomatous Survival of Mycobacterium tuberculosis
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DOI：
10.1165/rcmb.2016-0239oc
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发表时间：
2017-05-01
影响因子：
6.4
通讯作者：
Kaushal, Deepak
中科院分区：
文献类型：
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作者：
Hudock, Teresa A.;Foreman, Taylor W.;Kaushal, Deepak
虽然它是公认的肉芽肿内的环境深刻地影响结核分枝杆菌（Mtb）和感染的结果，我们的能力，了解Mtb基因表达在这些壁龛一直是有限的。我们确定了来自活动性结核病（ATB）和潜伏性结核病感染（LTBI）的非人灵长类动物的类人肺病变中的肉芽肿内基因表达。我们采用了一种非激光为基础的方法，显微解剖个别肺病变和查询全球转录组的结核杆菌肉芽肿内。鉴定了在具有中央干酪样坏死的典型肉芽肿中以及在干酪本身中表达的Mtb基因，并与ATB（n = 7）或LTBI（n = 7）动物中的其他Mtb病变进行了比较。使用寡核苷酸方法和RT-PCR对猕猴样品以及使用人TB样品对结果进行验证。我们在ATB和LTBI病变中分别检测到约2，900和1，850个统计学显著的基因（微阵列分析的线性模型，Bonferroni校正，P <0.05）。在这些基因中，约1，300（ATB）和900（LTBI）的表达被阳性诱导。我们确定了关键调节子的诱导，并将我们的结果与先前确定的结核分枝杆菌生长所需的基因进行了比较。我们的研究结果表明，结核分枝杆菌用于确保其生存在一个高度紧张的环境在体内的途径。ATB和LTBI肉芽肿中通常表达大量基因。此外，休眠生存调节子的表达增强是LTBI动物病变的一个关键特征，强调了其在慢性感染阶段Mtb持续存在的重要性。
Although it is accepted that the environment within the granuloma profoundly affects Mycobacterium tuberculosis (Mtb) and infection outcome, our ability to understand Mtb gene expression in these niches has been limited. We determined intragranulomatous gene expression in human-like lung lesions derived from nonhuman primates with both active tuberculosis (ATB) and latent TB infection (LTBI). We employed a non-laser-based approach to microdissect individual lung lesions and interrogate the global transcriptome of Mtb within granulomas. Mtb genes expressed in classical granulomas with central, caseous necrosis, as well as within the caseum itself, were identified and compared with other Mtb lesions in animals with ATB (n = 7) or LTBI (n = 7). Results were validated using both an oligonucleotide approach and RT-PCR on macaque samples and by using human TB samples. We detected approximately 2,900 and 1,850 statistically significant genes in ATB and LTBI lesions, respectively (linear models for microarray analysis, Bonferroni corrected, P < 0.05). Of these genes, the expression of approximately 1,300 (ATB) and 900 (LTBI) was positively induced. We identified the induction of key regulons and compared our results to genes previously determined to be required for Mtb growth. Our results indicate pathways that Mtb uses to ensure its survival in a highly stressful environment in vivo. A large number of genes is commonly expressed in granulomas with ATB and LTBI. In addition, the enhanced expression of the dormancy survival regulon was a key feature of lesions in animals with LTBI, stressing its importance in the persistence of Mtb during the chronic phase of infection.