# Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis
## 7 Deciphering the Roles of TA Modules in Pathogenicity
### TAs in Virulent Enterobacteriaceae: Escherichia coli and Salmonella typhimurium  
TA genes were first described on plasmids resident in _E. coli_[169; 170]. Much of the intervening research on elucidating the functional, biochemical and structural features of TA complexes has centered on the well-characterized _E. coli_ K-12 laboratory strain [6; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180] (Figure 2). However, _E. coli_ species are very diverse genetically and encompass both commensal and pathogenic strains. The latter may cause intestinal and extraintestinal infections of varying severity. Uropathogenic _E. coli_ (UPEC) are a sub-category of the extraintestinal group and are responsible for the majority of urinary tract infections (UTI) in humans [181]. Individual deletions of the seven type II TA loci from a UPEC strain revealed that only mutants lacking the _pasTI_ (also known as _ffjGF_) genes were outcompeted by the wild type strain in the kidneys, but not in the bladder, in a mouse UTI model system. The _pasTI_ deletion also reduced kidney colonization under non-competitive conditions. The deletion strain colonized the mouse gastrointestinal tract normally [182]. Thus, the _pasTI_ genes may play a crucial role in UPEC migration from the lower to upper urinary tract. The mechanism by which the _pasTI_ locus mediates kidney colonization is unknown. However, as the genes are vital for persister cell formation by the UPEC strain, but not the K-12 strain, under laboratory conditions and also participate in stress resistance of UPEC strains _in vitro_, the complex may help UPEC strains to overcome defensive host factors including amino acid limitation and oxidative and nitrosative stresses [182]. Binding of the PasT toxin (also known as RatA) to the 50S subunit of the bacterial ribosome blocks its interaction with the 30S subunit. PasT-mediated inhibition of the formation of 70S ribosomes thus prevents translation initiation [183]. It remains to be resolved how this activity integrates with kidney colonization by UPEC strains, but down-regulation of protein synthesis may be highly advantageous under specific stress conditions that these strains encounter within certain host niches in the urinary tract. In contrast with _pasTI_, deletion of either the _yeffM-yoeB_ or _lha-tomB_ (also known as _lha-ybaJ_) TA loci in a UPEC strain reduced competitiveness in the bladder, but not in the kidneys, in a mouse UTI model [182]. As noted above, transcriptional repression of certain rare codon tRNAs by the Hha toxin inhibits the production of surface fimbiae that are essential for biofilm formation by pathogenic _E. coli_[75]. The TomB protein blocks the activity of Hha (Figure 3). Transcriptional repression of rare codon tRNAs by Hha also induces production of prophage lysis genes as well as the ClpP/ClpX proteases that liberate the toxin components of other TA complexes by antitoxin degradation. Cell lysis and biofilm disruption ensue which may explain the impaired competitiveness of the UPEC strain in bladder colonization [75]. _S. typhimurium_ is a major foodborne pathogen. The chromosome of _S. typhimurium_ possesses at least six putative or established type I modules and 17 type II TA modules [128; 184]. Individual deletions of type II TA loci modestly reduced replication of _S. typhimurium_ in bone marrow-derived macrophages and decreased persister cell formation [128]. In a separate study, certain type I and type II TAs were shown also to differentially modulate _S. typhimurium_ survival in fibroblast and epithelial cell lines [184]. The type II TAs in _S. typhimurium_ include a functional _bigBA_ locus denoted _sethAB_[185]. Transcription of _sethAB_ increases when _S. typhimurium_ is cultivated under laboratory conditions that are known to activate genes involved in intracellular proliferation. Although the genes also are up-regulated in mouse macrophages that are infected with _S.