Replication dynamics of Mycobacterium tuberculosis in chronically infected mice?
Replication dynamics of Mycobacterium tuberculosis in chronically infected mice?
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DOI：
10.1128/iai.73.1.546-551.2005
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
McKinney, JD
中科院分区：
文献类型：
--
作者：
Muñoz-Elías, EJ;Timm, J;McKinney, JD
宿主-病原体相互作用的动力学对于设计新的抗微生物剂以治疗慢性感染如结核病（TB）具有重要意义，结核病是众所周知的常规药物治疗难治性。在TB的小鼠模型中，肺中细菌指数生长的急性期之后是以细菌数量相对稳定为特征的慢性期。这种平衡可以是静态的，几乎没有持续的复制，也可以是动态的，通过杀死细菌来平衡连续的细菌繁殖。静态模型预测随着时间的推移，肺中的“活菌计数”（活细菌）和“总计数”（活细菌加死细菌）之间的密切对应关系。动态模型预测由于死细菌的积累而导致的总计数和活计数随时间的发散。此处，活菌计数定义为通过平板接种肺匀浆计数的细菌CFU;总计数定义为通过使用定量实时PCR计数的细菌染色体当量（CEQ）。我们发现，在慢性感染小鼠的肺中的活菌和细菌总数不会随着时间的推移而发生变化。死亡细菌的快速降解不太可能解释肺部细菌CEQ数量随时间的稳定性，因为用异烟肼治疗小鼠8周导致CFU数量显著减少，而CEQ数量没有减少。这些观察结果支持了这样的假设：慢性感染期间肺部细菌CFU的稳定数量代表了宿主和病原体之间的静态平衡。
The dynamics of host-pathogen interactions have important implications for the design of new antimicrobial agents to treat chronic infections such as tuberculosis (TB), which is notoriously refractory to conventional drug therapy. In the mouse model of TB, an acute phase of exponential bacterial growth in the lungs is followed by a chronic phase characterized by relatively stable numbers of bacteria. This equilibrium could be static, with little ongoing replication, or dynamic, with continuous bacterial multiplication balanced by bacterial killing. A static model predicts a close correspondence between "viable counts" (live bacteria) and "total counts" (live plus dead bacteria) in the lungs over time. A dynamic model predicts the divergence of total counts and viable counts over time due to the accumulation of dead bacteria. Here, viable counts are defined as bacterial CFU enumerated by plating lung homogenates; total counts are defined as bacterial chromosome equivalents (CEQ) enumerated by using quantitative real-time PCR. We show that the viable and total bacterial counts in the lungs of chronically infected mice do not diverge over time. Rapid degradation of dead bacteria is unlikely to account for the stability of bacterial CEQ numbers in the lungs over time, because treatment of mice with isoniazid for 8 weeks led to a marked reduction in the number of CFU without reducing the number of CEQ. These observations support the hypothesis that the stable number of bacterial CFU in the lungs during chronic infection represents a static equilibrium between host and pathogen.