We developed an approach for substantial attenuation of Mycobacterium tuberculosis by prolonged culturing under gradually acidifying conditions. Bacteria subjected to acidification lost the capacity to form colonies on solid media, but readily resuscitated their growth in the murine host, providing a useful model to study in vivo development of infection mimicking latent and reactivation tuberculosis (TB) in humans. Here we characterize biomarkers of lung pathology and immune responses triggered by such attenuated bacteria in genetically TB-susceptible and resistant mice. In susceptible I/St mice, CFU counts in lungs and spleens were ~1.5-log higher than in resistant B6 mice, accompanied by diffuse pneumonia and excessive lung infiltration with highly activated CD44⁺CD62L^- T-lymphocytes resulting in death between months 7–9 post challenge. B6 mice were characterized by development of local inflammatory foci, higher production of pro-inflammatory IL-6 and IL-11 cytokines and a more balanced T-cell activation in their lungs. CFU counts remained stable in B6 mice during the whole 18-mo observation period, and all mice survived. Thus, we established a mouse model of fatal reactivation TB vs. indefinite mycobacterial possession after identical challenge and characterized the features of immune responses in the lung tissue underlining these polar phenotypes.

我们开发了一种通过在逐渐酸化的条件下长时间培养来实质性减轻结核分枝杆菌的方法。经受酸化作用的细菌丧失了在固体培养基上形成菌落的能力，但是很容易恢复了它们在鼠宿主中的生长，为研究体内模仿人的潜伏性和活化性结核病（TB）的感染提供了有用的模型。在这里，我们表征了在遗传性结核病易感和耐药小鼠中这种减毒细菌触发的肺部病理学和免疫反应的生物标志物。在易感的I / St小鼠中，肺和脾脏的CFU计数比耐药B6小鼠高约1.5对数，伴有弥漫性肺炎和肺过度浸润，CD44 ⁺CD62L ^- T淋巴细胞导致攻击后7到9个月之间死亡。B6小鼠的特征是局部炎症灶的发展，促炎性IL-6和IL-11细胞因子的更高产生以及肺中T细胞活化的更平衡。在整个18个月的观察期内，B6小鼠的CFU计数保持稳定，并且所有小鼠均存活。因此，我们建立了致命性激活TB vs.的小鼠模型。在相同的攻击后不确定的分枝杆菌拥有，并表征了这些极性表型的肺组织免疫应答的特征。