Mathematical modeling suggests heterogeneous replication of Mycobacterium tuberculosis in rabbits

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Abstract Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains the major health problem. We performed experiments with rabbits infected with a novel, virulent clinical Mtb isolate of the Beijing lineage HN878 carrying an unstable plasmid pBP10, allowing us to quantify how quickly HN878 replicates and dies in lungs of rabbits. In our in vitro experiments we found that pBP10 is more stable in HN878 strain than in a more commonly used laboratory-adapted H37Rv strain (the segregation coefficient being s=0.10 in HN878 vs. s=0.18 in H37Rv). Interestingly, the kinetics of the frequency of plasmid-bearing bacteria in lungs of Mtb-infected rabbits did not follow an expected monotonic decline; the percent of Mtb-bearing cells increased between 4 and 8 weeks post-infection and remained stable between 12 and 18 weeks post-infection despite a large increase in bacterial numbers in the lung at these 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 kinetics: one major population expanding early and being controlled, while another, a smaller population expanding at later times causing a counterintuitive increase in the percent of plasmid-bearing cells. Given that HN878 forms well circumscribed granulomas in rabbits, our results suggest independent bacterial dynamics in subsets of such granulomas. Our model predictions can be tested in experiments in which HN878-pBP10 dynamics in individual granulomas is followed over time. 1R01AI158963-01A1