The role of resuscitation promoting factors in pathogenesis and reactivation of Mycobacterium tuberculosis during intra-peritoneal infection in mice

Abstract

Background: Mycobacterium tuberculosis can enter into a dormant state which has resulted in one third of the world's population being infected with latent tuberculosis making the study of latency and reactivation of utmost importance. M. tuberculosis encodes five resuscitation promoting factors (Rpfs) that bear strong similarity to a lysozyme-like enzyme previously implicated in reactivation of dormant bacteria in vitro.

Cell Wall Deficiency in Mycobacteria: Latency and Persistence

“…Recently, it has been found that bacteria possess a specific system for autoregulation of growth and development, which participates in control of cell differentiation at the level of regulation of the functional activity of subcellular components and of the cell as a whole (Shleeva et al, 2010). Resuscitation-promoting factors have also been identified and their role in latency and reactivation of tuberculosis have been investigated (Biketov et al, 2007;Zhang et al, 2001;). Five genes encoding Rpf-like proteins have been found in M. tuberculosis genome, which may act in reactivation of "nonculturable " forms of M. tuberculosis (Kana et al, 2008;Mukamolova et al, 2002;Tufariello et al, 2004).…”

Resuscitation-promoting factors are important determinants of the pathophysiology inMycobacterium tuberculosisinfection

“…In one study of mice infected with rpf double deletion mutants via the respiratory tract, only the DrpfAB mutant showed lower lung and spleen colony forming units (CFUs) versus the wild type Mtb strain (Russell-Goldman et al, 2008). This contrasts with an intraperitoneal model of infection where DrpfAC was more attenuated for growth than DrpfAB although differences in host, strain or experimental conditions may account for this (Biketov et al, 2007). With triple rpf deletion mutants, the loss of rpfB from a DrpfAC mutant was more attenuating for growth in the mouse lung than rpfD loss (Downing et al, 2005).…”

“…When single rpf genes are deleted, there is no impact on the course of acute infection or the immunopathology witnessed, perhaps indicating physiological redundancy (Gupta & Srivastava, 2012). However, further deletion of rpf genes reduces Mtb virulence which manifests as reduced growth and dissemination from the site of primary infection (Biketov et al, 2007;Kana et al, 2008;Kondratieva et al, 2011;Russell-Goldman et al, 2008). Ultimately, the mortality of mice infected with attenuated rpf deletion mutants is lower (Kondratieva et al, 2011;Russell-Goldman et al, 2008).…”

“…Single rpf deletion mutants do not exhibit persistence defects, however with the progressive deletion of rpf genes, replication is impaired. These mutants require more time to establish chronic infection and replicate less compared to the wild type background strain (Biketov et al, 2007;Kana et al, 2008;Russell-Goldman et al, 2008;Tufariello et al, 2006). Notably, the effect of individual rpf deletions varies with the loss of rpfD from the mutant DrpfACB less impactful than rpfE (Kana et al, 2008).…”

“…When single rpf genes are deleted, only rpfB deficiency delays recrudescence (Tufariello et al, 2006). Progressive rpf deletion reduces the rise in CFU counts with immunosuppression with triple rpf deletion mutants exhibiting no rise at all (Biketov et al, 2007;Russell-Goldman et al, 2008).…”