Understanding the biology of the tuberculosis pathogen during dormant asymptomatic infection, called latent tuberculosis is crucial to decipher a resilient therapeutic strategy for the disease. Recent discoveries exhibiting presence of pathogen’s DNA and bacilli in mesenchymal stem cells (MSCs) of human and mouse despite completion of antitubercular therapy, indicates that these specific cells could be one of the niches for dormant Mycobacterium tuberculosis in humans. To determine if in vitro infection of human MSCs could recapitulate the in vivo characteristics of dormant M. tuberculosis, we examined survival, phenotype, and drug susceptibility of the pathogen in MSCs. When a very low multiplicity of infection (1:1) was used, M. tuberculosis could survive in human bone marrow derived MSCs for more than 22 days without any growth. At this low level of infection, the pathogen did not cause any noticeable host cell death. During the later phase of infection, MSC-residing M. tuberculosis exhibited increased expression of HspX (a 16-kDa alpha-crystallin homolog) with a concurrent increase in tolerance to the frontline antitubercular drugs Rifampin and isoniazid. These results present a human MSC-based intracelllular model of M. tuberculosis infection to dissect the mechanisms through which the pathogen acquires and maintains dormancy in the host.

了解潜伏性结核在休眠无症状感染期间的结核病病原体生物学对于破译该疾病的弹性治疗策略至关重要。尽管完成了抗结核治疗，但最近发现在人和小鼠的间充质干细胞 (MSC) 中仍存在病原体的 DNA 和杆菌，这表明这些特定细胞可能是人类休眠结核分枝杆菌的生态位之一。为了确定人 MSC 的体外感染是否可以重现休眠结核分枝杆菌的体内特征，我们检查了 MSC 中病原体的存活率、表型和药物敏感性。当使用非常低的感染复数 (1:1) 时，结核分枝杆菌可以在人骨髓来源的 MSC 中存活超过 22 天而没有任何生长。在这种低感染水平下，病原体不会引起任何明显的宿主细胞死亡。在感染的后期阶段，驻留在MSC 的结核分枝杆菌表现出 HspX（一种 16-kDa α-晶状体蛋白同源物）的表达增加，同时对一线抗结核药物利福平和异烟肼的耐受性增加。这些结果提出了一种基于人类 MSC 的结核分枝杆菌感染细胞内模型，以剖析病原体在宿主中获得和维持休眠的机制。