Replication Dynamics of Mycobacterium tuberculosis in Chronically Infected Mice

Abstract

The dynamics of host-pathogen interactions have important implications for the design of new antimicrobial agents to treat chronic infections such as tuberculosis (TB), which is notoriously refractory to conventional drug therapy. In the mouse model of TB, an acute phase of exponential bacterial growth in the lungs is followed by a chronic phase characterized by relatively stable numbers of bacteria. This equilibrium could be static, with little ongoing replication, or dynamic, with continuous bacterial multiplication balanced by bacterial killing. A static model predicts a close correspondence between "viable counts" (live bacteria) and "total counts" (live plus dead bacteria) in the lungs over time. A dynamic model predicts the divergence of total counts and viable counts over time due to the accumulation of dead bacteria. Here, viable counts are defined as bacterial CFU enumerated by plating lung homogenates; total counts are defined as bacterial chromosome equivalents (CEQ) enumerated by using quantitative real-time PCR. We show that the viable and total bacterial counts in the lungs of chronically infected mice do not diverge over time. Rapid degradation of dead bacteria is unlikely to account for the stability of bacterial CEQ numbers in the lungs over time, because treatment of mice with isoniazid for 8 weeks led to a marked reduction in the number of CFU without reducing the number of CEQ. These observations support the hypothesis that the stable number of bacterial CFU in the lungs during chronic infection represents a static equilibrium between host and pathogen.

In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice

“…Silencing of prcBA transcription during mouse infections demonstrated that the Mtb proteasome is not only required for optimal in vivo growth but is also essential during the chronic phase of the infection, when the pathogen replicates slowly or not at all 31,32 . The eukaryotic proteasome participates in protein turnover, transcription and DNA repair 33 .…”

Insights on the paleoepidemiology of ancient tuberculosis from the structural analysis of postcranial remains from the Ligurian Neolithic (northwestern Italy)

“…Changes in the pathogen as well as host immunity may significantly alter TB morbidity and virulence over a relatively short period of time (Palkovich, 1981). In particular, murine models suggest that the chronic slow progression of TB is not due to slow replication of the bacterium itself, but to the ability of the localized immune response to maintain equilibrium and latency (Munoz-Elias et al, 2005;Ulrichs et al, 2005;Gill et al, 2009). There is also clinical evidence suggesting that the host response plays a major role in restricting intracellular mycobacterial growth and therefore in determining the clinical manifestations of the disease (Schluger and Rom, 1998).…”

Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice

“…In the i.v. infection model, bacteria replicate exponentially in the lungs for the first 2 wk postinfection; thereafter, bacterial numbers remain relatively stable for several months (6)(7)(8). From 4 wk onward, half of the mice were treated with INH.…”

“…Although these drugs rapidly kill Mycobacterium tuberculosis grown in vitro, they are less active against bacteria grown in vivo in mammalian hosts (4,5). In the mouse model of TB, infection progresses through a brief acute phase, when bacteria replicate exponentially in the lungs, to a protracted chronic phase, when growth slows and bacterial numbers are stabilized by the immune response (6)(7)(8). Anti-TB drugs like INH display good bactericidal activity in acutely infected mice, but chronic infection is more refractory (9).…”