IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1012563.html
   My bibliography  Save this article

Mathematical modeling suggests heterogeneous replication of Mycobacterium tuberculosis in rabbits

Author

Listed:
  • Vitaly V Ganusov
  • Afsal Kolloli
  • Selvakumar Subbian

Abstract

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”.Author summary: How quickly Mycobacterium tuberculosis (Mtb) replicates and dies in lungs of infected individuals is likely to determine the outcome of the infection—either control/clearance of the bacteria by the host immune response or progression to active disease, tuberculosis (TB). And yet, only a few studies, primarily in mice, rigorously estimated the rates of Mtb replication and death during an in vivo infection. We infected rabbits with a novel clinical isolate of Mtb carrying an unstable, “replication clock” plasmid and followed the dynamics of bacteria over time. Interestingly, previous methods developed to estimate Mtb replication and death rates using similar data for Mtb infection of mice failed to describe our novel data on Mtb dynamics in rabbits; we showed that heterogeneous dynamics of Mtb in semi-independent subpopulations in lungs of Mtb-infected rabbits may be one explanation of this failure of the method. Our results highlight potential differences in Mtb dynamics in different mammalian hosts and suggest ways to evaluate heterogeneity of Mtb replication and death rates in vivo.

Suggested Citation

  • Vitaly V Ganusov & Afsal Kolloli & Selvakumar Subbian, 2024. "Mathematical modeling suggests heterogeneous replication of Mycobacterium tuberculosis in rabbits," PLOS Computational Biology, Public Library of Science, vol. 20(11), pages 1-25, November.
  • Handle: RePEc:plo:pcbi00:1012563
    DOI: 10.1371/journal.pcbi.1012563
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1012563
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1012563&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1012563?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pcbi00:1012563. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.