Mathematical modeling suggests that Mycobacterium tuberculosis CFU/CEQ ratio is not a robust indicator of cumulative bacteria killing

AllanFriesen

Texas Biomedical Research Institute

"Mathematical modeling suggests that Mycobacterium tuberculosis CFU/CEQ ratio is not a robust indicator of cumulative bacteria killing"

Correlates of protection against infection with Mycobacterium tuberculosis (Mtb) or against tuberculosis (TB) remain poorly defined. The ratio of colony forming units (CFUs) to chromosomal equivalents (CEQs), Z = CFU/CEQ, has been used as a metric for how effectively Mtb is killed in vivo. However, the contribution of bacterial killing to changes in CFU/CEQ ratio during an infection has not been rigorously investigated. We developed alternative mathe- matical models to study the dynamics of CFUs, CEQs, and Z during an Mtb infection. We find that the ratio Z alone cannot be used to infer the death rate of bacteria, unless the dynamics of CEQs and CFUs are entirely uncoupled, which is biologically unreasonable and inconsistent with the view that CEQs reflect an accumulation of both viable and non-viable bacteria. We estimate a half life of about 20 days of Mtb H37Rv CEQs in mice, similar to that found for Mtb Erdman in cynomolgus macaques. Although this seems slow, we found that estimated rates of Mtb replication and death are extremely sensitive even to slow decay of detectable Mtb genomes. We provide evidence of substantial killing of Mtb bacteria prior to arrival of adaptive immunity to the site of infection. We also propose experiments that will allow to more accurately measure the rate of Mtb DNA loss helping more rigorously to quantify impact of immunity on within-host Mtb dynamics.
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