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The genus  Salmonella  includes many pathogens of great medical and veterinary importance. Bacteria belonging to this genus are very closely related to those belonging to the genus  Escherichia .  lacZYA  operon and  lacI  are present in  Escherichia coli,  but not in  Salmonella enterica . It has been proposed that  Salmonella  has lost  lacZYA  operon and  lacI  during evolution. In this study, we have investigated the physiological and evolutionary significance of the absence of  lacI  in  Salmonella enterica . Using murine model of typhoid fever, we show that the expression of LacI causes a remarkable reduction in the virulence of  Salmonella enterica . LacI also suppresses the ability of  Salmonella enterica  to proliferate inside murine macrophages. Microarray analysis revealed that LacI interferes with the expression of virulence genes of  Salmonella  pathogenicity island 2. This effect was confirmed by RT-PCR and Western blot analysis. Interestingly, we found that SBG0326 of  Salmonella bongori  is homologous to  lacI  of  Escherichia coli .  Salmonella bongori  is the only other species of the genus  Salmonella  and it lacks the virulence genes of  Salmonella  pathogenicity island 2. Overall, our results demonstrate that LacI is an antivirulence factor of  Salmonella enterica  and suggest that absence of  lacI  has facilitated the acquisition of virulence genes of  Salmonella  pathogenicity island 2 in  Salmonella enterica  making it a successful systemic pathogen.

lac Repressor Is an Antivirulence Factor of Salmonella enterica: Its Role in the Evolution of Virulence in Salmonella