# Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis
## 7 Deciphering the Roles of TA Modules in Pathogenicity  
### Mycobacterium tuberculosis: TA Proteins, Infection and Dormancy  
_M. tuberculosis_ causes a serious and prolonged pulmonary infection that has a high mortality rate if untreated [131]. In addition to strategies that promote the evasion of host immune defenses, entry of a subpopulation of cells into a dormant state is a major factor in the protracted infection induced by _M. tuberculosis_. Intermittent reawakening of this reservoir of latent infection triggers the recurrent relapses that typify the disease [132]. The rise of antibiotic resistant strains of _M. tuberculosis_, which in certain cases are resistant to multiple drugs, adds another challenging layer of difficulty to tuberculosis treatment [133]. As described above, TA modules are stress response elements that damp physiological activity by, for example, inhibiting protein translation. A potential outcome of this metabolic shutdown is entrance into a persistent state in which cells are tolerant of antibiotics [64; 102]. Analogously, the dormant state in _M. tuberculosis_ is characterized by low metabolic activity and consequent insensitivity to antibiotic treatment. There is emerging evidence that latency in _M. tuberculosis_ and persistence may be related phenomena that are mediated in part by TA cassettes through their roles in modulating physiological activity [134; 135]. Indeed TA proteins are enriched in nutrient-starved cultures of _M. tuberculosis_, which suggests a role for TAs in progression into dormancy [136]. Intriguingly, _M. tuberculosis_ harbors the most putative TA genes (>80) on a single genome that have been catalogued to date among bacterial species, although the functions of many of these genes remain unclear [39; 137]. Some of the encoded TA cassettes, including certain VapBC modules which are the most abundant TAs in _M. tuberculosis_, have been characterized genetically and biochemically and have provided general insights into TA activity. For example, numerous _M. tuberculosis_ toxins are sequence-specific endoribonucleases that cleave mRNA and are counteracted by the cognate antitoxins [138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151]. In contrast, a VapC homologue instead was shown recently to inhibit translation by cutting specifically a subset of mycobacterial tRNAs [152]. Elucidation of the tertiary structure of a mycobacterial VapBC complex led to the design of custom peptides that interfere with formation of the complex [153]. Moreover, degradation of a HigA antitoxin of _M. tuberculosis_ unexpectedly was inhibited by a chaperone protein, which may reflect a broader role for chaperones in regulating TA activity [154; 155]. In addition to investigating TA activity and diversity in _M. tuberculosis_, numerous strands of evidence support a role for TAs in mycobacterial pathogenesis. The bacterium encodes two functional _relBE_ cassettes and one _yefM-yoeB_ module [39; 133; 156]. The RelE and YoeB toxins are homologues, whereas the RelB and YefM antitoxins are unrelated [157; 158]. The mycobacterial _relBE_ and _yefM-yoeB_ operons are up-regulated in response to nitrogen starvation and oxidative stress, and down-regulated in response to hypoxia [133; 137; 159]. These conditions are relevant to those prevailing during _M. tuberculosis_ infection. Increased expression of one of the numerous mycobacterial _vapBC_ homologues as well as a _higBA_ locus also occurs during hypoxia [137]. Similarly, enhanced expression of the _relE_ and _yoeB_ toxin genes is evident following exposure to certain antibiotics, which consequently promotes entry into a persistent state under laboratory conditions [125; 143; 160]. However, deletion of the homologues affected neither mycobacterial survival nor persistence in mice [125]. In contrast, although expression of the _relBE_ and _yefM-yoeB_ genes was not detectable in the early or middle stages of infection following phagocytosis of _M.