Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing
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DOI：
10.1038/nm.3412
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发表时间：
2014-01-01
期刊：
影响因子：
82.9
通讯作者：
Flynn, JoAnne L.
中科院分区：
文献类型：
--
作者：
Lin, Philana Ling;Ford, Christopher B.;Flynn, JoAnne L.
超过30%的世界人口感染结核分枝杆菌（Mtb），但只有大约5-10%的人会发展成临床疾病（1）。尽管付出了相当大的努力，但研究人员对感染进展为活动性结核病（TB）的个体与感染潜伏数十年的个体的区别知之甚少。在感染Mtb的食蟹猴中重现了不同的病程（2）。活动性疾病发生在类似于45%的感染猕猴中，并通过临床、微生物学和免疫学体征来定义，而其余感染动物在临床上无症状（2，3）。在这里，我们使用单独标记的结核分枝杆菌分离株和可培养和累积细菌负荷的定量测量，以表明大多数肺部病变可能是由单一细菌建立的，并达到相似的最大负荷。尽管如此，在同一宿主中，单个病变的命运差异很大。值得注意的是，在活动性疾病中，即使在其他病变进展时，宿主也会使一些病变绝育。我们的数据表明，病变的异质性，部分原因是通过差异杀死细菌后，适应性免疫的发病。因此，单个病变遵循不同的和重叠的轨迹，这表明关键的反应发生在病变水平，以最终确定感染的临床结果。确定决定结果的当地因素将有助于制定有效的干预措施，以预防活动性结核病。
Over 30% of the world's population is infected with Mycobacterium tuberculosis (Mtb), yet only similar to 5-10% will develop clinical disease(1). Despite considerable effort, researchers understand little about what distinguishes individuals whose infection progresses to active tuberculosis (TB) from those whose infection remains latent for decades. The variable course of disease is recapitulated in cynomolgus macaques infected with Mtb(2). Active disease occurs in similar to 45% of infected macaques and is defined by clinical, microbiologic and immunologic signs, whereas the remaining infected animals are clinically asymptomatic(2,3). Here, we use individually marked Mtb isolates and quantitative measures of culturable and cumulative bacterial burden to show that most lung lesions are probably founded by a single bacterium and reach similar maximum burdens. Despite this observation, the fate of individual lesions varies substantially within the same host. Notably, in active disease, the host sterilizes some lesions even while others progress. Our data suggest that lesional heterogeneity arises, in part, through differential killing of bacteria after the onset of adaptive immunity. Thus, individual lesions follow diverse and overlapping trajectories, suggesting that critical responses occur at a lesional level to ultimately determine the clinical outcome of infection. Defining the local factors that dictate outcome will be useful in developing effective interventions to prevent active TB.