## 2 GidA/MnmE-Associated Virulence of Gram-Negative Bacteria
An additional study showed that GidA protein expression was significantly increased under certain growth conditions (1% glucose, pH 5, 100 \(\upmu\)M EDTA). Furthermore, this study showed that the increase in GidA expression correlated with increased _in vitro Salmonella_ virulence as indicated by increased motility and cytotoxicity of macrophages [39]. Stress response systems play a crucial role in the virulence of pathogenic organisms [60,61]. The ability of bacteria to recognize and respond to adverse environments is required for their survival. These responses require a wide variety of global regulatory network systems [60,61]. In order to survive and establish infection, _Salmonella_ and other bacteria must overcome a range of stress conditions including external environments, food matrices, and the _in vivo_ host environment such as ability to survive inside macrophages [60,61]. A _Salmonella gidA_ mutant showed a significant decrease in ability to survive and replicate inside macrophages and in a mouse model of infection [38]. Most importantly, expression of several stress related genes such as carbon starvation (_cstA_), putative universal stress (_ynaF_ and _yecG_), heat shock (_hsIO_), and cold-shock (_cspH_) genes were significantly altered in a _gidA_ mutant, compared to the WT suggesting an important role for GidA in the response to these particular stressors [38]. Similarly, proteome analysis of a _gidA_ mutant revealed down-regulation in expression of several proteins involved in survival of _Salmonella_ to stressful conditions inside host macrophages such as the oxidoreductase YghA, and the thiol peroxidase Tpx [38]. To examine the potential GidA functional interactions with other proteins in _Salmonella_, [PERSON] _et al._ performed bioinformatic analysis using STRING 8.3 software [30]. Data from this analysis strongly suggest that GidA interacts with several other _Salmonella_ proteins involved in stress response and replication (e.g., DnaA and DnaN) and RNA modification enzymes (MnmE, MnmA, and RsmG). On the other hand, MnmE interacts, in addition to GidA, with RNA modification enzymes (MnmA,RluD), stress and replication related proteins (DnaA, YhbZ, GyrB). These data strongly suggest a role for the GidA and MnmE in stress responses. Additionally, the study by [PERSON] _et al._ suggests MnmE is part of a regulatory system which modulates the small alarmone ppGpp to coordinate _Francisella tulareis_ gene expression in response to the numerous nutritional and cellular stresses present in different mammalian cells [43]. Several reports show the potential contribution of GidA and MnmE to the pathogenesis of other Gram-negative bacteria. A recent study by [PERSON] _et al._ suggests GidA and MnmE are positive regulatory elements that regulate the production of 2,4-diacetylphloroglucinol (2,4-DAPG) using a post-transcriptional mechanism in an important plant growth-promoting rhizobacteria, _Pseudomonas fluorescens_[41]. Both _gidA_ and _mnmE_ deletion mutants were unable to produce phloroglucinol (PG), but could convert PG to monoacetylphloroglucinol (MAPG) and MAPG to 2,4 DAPG suggesting a pathway independent of the Gac/Rsm two-component system [41]. These findings offer insight into the regulation of secondary metabolites, like 2,4-DAPG, which displays antimicrobial activity, as well as other functions important for plant growth and health [62, 63, 64]. In another plant pathogen, _Pseudomonas syringae_, GidA is hypothesized to be a global regulator of _P. syringae_, as deletion of _gidA_ resulted in phenotypes associated with mutations of two-component regulators _gacS_ and _gacA_[42, 65, 66]. In their study, a _gidA_ deletion mutant lost the ability to produce the lipodepsipetide antibiotics syringomycin and syringopeptin as well as the ability to swarm across the surface of low agar media [42]. Additionally, deletion of _gidA_ attenuated the organism, but not to the extent seen in _gacS_, _gacA_, or _salA_ deletion mutants [42, 67]. In a different study in _P.