## 3 Conclusions  
An infectious process requires a constant adaptation of the bacteria to the different environments encountered within the host. During this adaptive response, bacteria undergo severe reprogramming that affects genes from virtually all the functional categories. In many pathogens, genes that encode functions directly implicated in the pathogenesis have been acquired by horizontal gene transfer (HGT) mechanisms [32].  
An intense interplay among core genome-encoded regulators and HGT-genetic systems exists. Most studies have focused on silencing systems, mediated by core genome-encoded regulators that suppress uncontrolled expression of newly arrived genetic systems to promote establishment of the new genes in the genome. These mechanisms are exemplified by the H-NS-mediated silencing of HGT-DNA described in different bacterial  
Figure 6: The UPEC-induced cytotoxicity on bladder epithelial cells is reduced in ppGpp-deficient derivatives by affecting production of \(\alpha\)-hemolysin. (**A**) Bacterial-induced cytotoxicity on T24 bladder epithelial cells was monitored as lactate dehydrogenase (LDH) activity released (OD\({}_{490\text{nm}}\)) after 3 h incubation with bacterial cultures (black bars) or cell-free supernatants (white bars). Bacterial cultures of the UPEC isolate J96 and its ppGpp-deficient derivative (J96 _reIA spO_, PPGpp\({}^{\text{0}}\)) were grown in LB at 37 \({}^{\circ}\)C up to late exponential phase (OD\({}_{600\text{nm}}\) of 0.8). The results are mean and standard deviation of four independent determinations. Statistical significance levels are reported as: \({}^{\star}=p<0.05\); \({}^{\star\star}=p<0.005\). (**B**) Coomassieie blue stained 12.5% SDS-PAGE analyses of cell-free supernatants from cultures used in A. Lane M: molecular mass markers (size in kDa indicated along the left side). (**C**) The expression of the two hemolytic operons, \(hlyCABD_{I}\) and \(hlyCABD_{II}\), present in the J96 strain is stimulated by ppGpp. Immunodetection of the secreted \(\alpha\)-hemolysin from cell-free supernatants of cultures of Wt and ppGpp\({}^{\text{0}}\) derivatives of \(96\Delta hyA_{II}\) (JFV16 and JFV18) and J96\(\Delta hyA_{I}\) (JFV21 and JFV22) grown in LB at 37 \({}^{\circ}\)C up to an OD\({}_{600\text{nm}}\) of 0.8. The band corresponding to the \(\alpha\)-hemolysin is indicated by an arrowhead.  
species [33]. Here, we described a core genome-encoded regulator, ppGpp, that stimulates the expression of a genetic system that has been acquired by HGT, the _hly_C_AB_D_II_ operon. This interplay ensures a positive stimulation of the expression of the newly acquired genes when required, thereby highlighting the importance of the responsiveness to stress sensors in the expression of colonization and/or virulence factors. The ppGpp-mediated stimulation of HGT gene systems related with virulence has also been described in other microorganisms such as _Salmonella_, where most of the genes present in the pathogenicity islands are under the control of ppGpp [34; 35; 9]. Our results suggest that, during the course of an infection, when bacteria encounter environmental and/or nutritional stress, the associated increase in the intracellular level of ppGpp causes a concomitant change in the gene expression pattern, reprogramming the bacterial metabolism, physiology, and pathogenicity, to promote survival of bacteria inside the host.