Mathematical modeling suggests heterogeneous replication of Mycobacterium tuberculosis in rabbits

Abstract Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains major health problem. We performed experiments with rabbits infected a novel, virulent clinical Mtb isolate of Beijing lineage HN878 carrying an unstable plasmid pBP10, allowing us to quantify how quickly replicates and dies in lungs rabbits. In our vitro we found that pBP10 is more stable strain than commonly used laboratory-adapted H37Rv (the segregation coefficient being s=0.10 vs. s=0.18 H37Rv). Interestingly, kinetics frequency plasmid-bearing bacteria Mtb-infected did not follow expected monotonic decline; percent Mtb-bearing cells increased between 4 8 weeks post-infection remained 12 18 despite large increase bacterial numbers lung at these time points. Mathematical modeling suggested such non-monotonic change can be explained if population consists several (at least 2) sub-populations different replication kinetics: one expanding early controlled, while another, smaller later times causing counterintuitive cells. Given forms well circumscribed granulomas rabbits, results suggest independent dynamics subsets granulomas. Our model predictions tested which HN878-pBP10 individual followed over time. 1R01AI158963-01A1