# Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis
## 5 Persistence Emerges in Response to the Activation of Diverse TA Modules
### Multiple Mechanisms for TA-Induced Persistence  
As described above, it is well established that type II endoribonuclease toxins inhibit general cellular protein synthesis, which leads to an increase in persister cell formation. However, it also has been demonstrated that induction of certain endoribonucleases leads to the enrichment or reduction of specific transcripts [63]. Accordingly, production of YafQ toxin increases persister cell formation through a significant reduction of tryptophanase (TnaA) levels caused by the fact that the _tnaA_ mRNA has 16 putative YafQ cleavage sites [114]. Furthermore, _tnaA_ is activated in the stationary phase by RpoS whereas YafQ reduces _rpoS_ expression indirectly by diminishing production of the CspC and CspE cold-shock proteins. Hence, the concomitant reduction in RpoS and TnaA protein levels by YafQ leads to reduced levels of indole which is the product of TnaA activity [114]. Indole is a quorum-sensing signal that influences multiple aspects of bacterial physiology and is an important factor in the transition from growth phase to the stationary phase (Figure 4).  
In contrast to the preceding activity of YafQ, the sequence-specific endoribonuclease activity of the MqsR toxin leads to the enrichment of certain transcripts that encode stress associated proteins. Moreover, persister cells produced by antibiotic stress induce MqsR, which influences production of other toxins, Hha and CspD [115; 116]. The _ghoT_ mRNA also is enriched by MqsR induction. The type V GhoST cassette increases persistence by damaging the cell membrane. The mechanism by which GhoT leads to the loss of membrane integrity and induces a dormant state probably relies on the modulation of proton pump activity or interaction with other membrane proteins. Since the activity of MqsR results in the enrichment of the transmembrane protein GhoT and also inhibits the expression of many genes, including these coding for the OmpA and OmpF outer membrane proteins, it may indicate that MqsR increases persistence through a tight control of membrane permeability [117; 118].  
The _tisB/istR1_ module of _E. coli_ (Figure 2) is a type I TA that is involved in the persistence phenotype under conditions of SOS induction [119]. The hydrophobic transmembrane peptide toxin TsB induces persister cell formation by decreasing both the proton motive force and ATP levels upon antibiotic stress, thus leading to the promotion of a dormant state. Similar to GhoT, the activity of TsB leads to damage of the inner membrane. TsB-dependent persisters were observed only in exponential growth when the SOS regulon is maximally expressed upon DNA damage [120]. Interestingly, the SOS response system also activates several other TA genes in _E. coli_, whose promoters contain a motif that may be recognized by the LexA transcriptional repressor: _symER_, _hokE_ and _yafN/yafO_[121].  
The type I _hokB_ toxin gene induces bacterial multidrug tolerance in a (p)ppGpp-dependent manner, via transcriptional activation by universally conserved GTPase ObgE (also known as CgtA). The HokB peptide provokes a collapse in the bacterial membrane potential. However, moderate levels of HokB cause membrane depolarization, which does not kill cells, but ultimately results in persistence [94; 122]. Collectively, the preceding findings show that certain membrane-acting toxin proteins are elements that are actively involved in persistence (Figure 4).  
Plasmid encoded TA systems are loci that stabilize these elements in bacteria. However, it was shown that the _ccd_ TA operon either located on a plasmid or on the _E. coli_ chromosome, also plays an indirect but significant role in the formation of persisters. Stress conditions activate Lon protease, which causes CcdA antitoxin degradation and release of CcdB toxin from the CcdA-CcdB complex. Free CcdB binds to its target, DNA gyrase, which induces the RecA-mediated SOS response and in turn activates other TA systems, finally leading to formation of persister cells [123].