# 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
tuberculosis_ by human macrophages, expression of genes encoding one of the two RelE toxins, the YoeB toxin, and one of the two RelB antitoxins was apparent in the late infection stage [156]. As macrophages fulfill a vital function in innate immunity by phagocytosis of infecting microbes, the expression of TA genes specifically at the late infection stage implicates the genes in mycobacterial survival in this hostile environment. _M. tuberculosis_ encodes ten MazEF homologues [39; 138; 161]. The biochemical features of several of these complexes have been investigated which has revealed that the mycobacterial MazF toxins are sequence-specific endoribonucleases that cleave mRNA, rRNA or tRNA and which are counteracted bythe cognate MazE antitoxins [40; 138; 140; 142; 145; 150; 162; 163; 164]. Individual MazF toxins are up-regulated in response to stresses that mimic those that occur during infection including nutrient depletion and hypoxia, as well as by antibiotic exposure and entry into a non-culturable state [136; 165; 166; 167]. Persister cell formation by _M. tuberculosis_ also is linked to _mazF_ expression [148; 161; 125; 135]. Moreover, expression of one of the _mazF_ homologues is coordinated with that of a gene that encodes a factor implicated in progression of the mycobacterial cell cycle. Elevated expression of both genes occurs for prolonged periods in the lungs and spleens of infected mice suggesting that this MazF homologue is involved in adaptation to the distinctive conditions that _M. tuberculosis_ encounters during colonization [167]. Intriguingly, three of the mycobacterial MazF toxins act cooperatively to provide protection during oxidative and antibiotic stresses, most likely by inhibiting metabolism and thereby inducing a persister-like state [161]. Simultaneous deletion of these _mazF_ homologues in _M. tuberculosis_ significantly reduced the bacterial load in infected guinea pigs compared to either the wild-type strain or strains deleted of single _mazF_ or _relE_ toxin genes. The concomitant reduced pathology by the triple deletion mutant strain was more pronounced in the spleen and the liver than in the lungs, which implies that MazF toxins may be involved in the spread of _M. tuberculosis_ from the lungs to other organs [161]. Expression of certain _vapBC_ loci in _M. tuberculosis_ is activated during macrophage infection or under hypoxic conditions [137]. TA loci, most notably certain _vapBC_ genes, also are up-regulated in drug-tolerant _M. tuberculosis_ isolated from patients [168]. Nevertheless, although 50 of the known TA modules in _M. tuberculosis_ are _vapBC_ homologues [135], there is scant additional evidence that implicates these complexes directly in mycobacterial pathogenesis. The numerous _vapBC_ genes may possess redundant or overlapping functions, which render it difficult to pinpoint a role in infection. Analogously, _M. tuberculosis_ harbors three _higBA_ loci but, apart from up-regulation in antibiotic-tolerant persister cells [135], there is no established role for these homologues in mycobacterial virulence.