Ganusov Vitaly V, Kolloli Afsal, Subbian Selvakumar
Host-Pathogen Interactions program, Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
Public Health Research Institute, The State University of New Jersey, Newark, New Jersey, United States of America.
PLoS Comput Biol. 2024 Nov 25;20(11):e1012563. doi: 10.1371/journal.pcbi.1012563. eCollection 2024 Nov.
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains a major health problem with 10.6 million cases of the disease and 1.6 million deaths in 2021. It is well understood that pulmonary TB is due to Mtb growth in the lung but quantitative estimates of rates of Mtb replication and death in lungs of patients or animals such as monkeys or rabbits remain largely unknown. We performed experiments with rabbits infected with a novel, virulent clinical Mtb isolate of the Beijing lineage, HN878, carrying an unstable plasmid pBP10. In our in vitro experiments we found that pBP10 is more stable in HN878 strain than in a more commonly used laboratory-adapted Mtb strain H37Rv (the segregation coefficient being s = 0.10 in HN878 vs. s = 0.18 in H37Rv). Interestingly, the kinetics of plasmid-bearing bacteria in lungs of Mtb-infected rabbits did not follow an expected monotonic decline; the percent of plasmid-bearing cells increased between 28 and 56 days post-infection and remained stable between 84 and 112 days post-infection despite a large increase in bacterial numbers in the lung at late time points. Mathematical modeling suggested that such a non-monotonic change in the percent of plasmid-bearing cells can be explained if the lung Mtb population consists of several (at least 2) sub-populations with different replication/death kinetics: one major population expanding early and being controlled/eliminated, while another, a smaller population expanding at later times causing a counterintuitive increase in the percent of plasmid-bearing cells. Importantly, a model with one kinetically homogeneous Mtb population could not explain the data including when the model was run stochastically. Given that in rabbits HN878 strain forms well circumscribed granulomas, our results suggest independent bacterial dynamics in subsets of such granulomas. Our model predictions can be tested in future experiments in which HN878-pBP10 dynamics in individual granulomas is followed over time. Taken together, our new data and mathematical modeling-based analyses illustrate differences in Mtb dynamics in mice and rabbits confirming a perhaps somewhat obvious observation that "rabbits are not mice".
结核病（TB）由结核分枝杆菌（Mtb）引起，仍然是一个重大的健康问题，2021年有1060万例该疾病，160万人死亡。众所周知，肺结核是由于Mtb在肺部生长所致，但对于患者或动物（如猴子或兔子）肺部中Mtb复制率和死亡率的定量估计在很大程度上仍不清楚。我们用感染了北京家族新型强毒临床Mtb分离株HN878的兔子进行了实验，该分离株携带不稳定质粒pBP10。在我们的体外实验中，我们发现pBP10在HN878菌株中比在更常用的实验室适应Mtb菌株H37Rv中更稳定（分离系数在HN878中为s = 0.10，在H37Rv中为s = 0.18）。有趣的是，Mtb感染兔子肺部中携带质粒细菌的动力学并未遵循预期的单调下降；携带质粒细胞的百分比在感染后28至56天之间增加，并且在感染后84至112天之间保持稳定，尽管后期肺部细菌数量大幅增加。数学模型表明，如果肺部Mtb群体由几个（至少2个）具有不同复制/死亡动力学的亚群体组成，那么携带质粒细胞百分比的这种非单调变化就可以得到解释：一个主要群体早期扩张并受到控制/消除，而另一个较小的群体在后期扩张，导致携带质粒细胞百分比出现违反直觉的增加。重要的是，具有一个动力学上均匀的Mtb群体的模型无法解释这些数据，包括当该模型进行随机运行时。鉴于在兔子中HN878菌株形成界限清楚的肉芽肿，我们的结果表明此类肉芽肿亚群中存在独立的细菌动态。我们的模型预测可以在未来的实验中进行检验，在这些实验中随着时间推移跟踪单个肉芽肿中HN878 - pBP10的动态。综上所述，我们的新数据和基于数学模型的分析说明了小鼠和兔子中Mtb动态的差异，证实了一个也许有点明显的观察结果，即“兔子不是小鼠”。
