In this context, S. Typhi represents an intermediate step between obligate bacterial parasites and free living bacteria, exhibiting some genome erosion directed to inactivate and lose detrimental or non-essential functions for their environment (i.e. host) [40]. Thus, we hypothesized that the loss of some of these genes contributed to the adaptation of S. Typhi to the systemic infection. Our results suggest that the loss of the fully functional SseJ protein in S. Typhi contributed to the adaptation to the systemic infection by increasing bacterial cytotoxicity in epithelial cells. The increased

cytotoxicity presented by S. Typhi compared with S. Typhimurium is not only buy Nutlin-3 related to the loss of functions, as we showed here with the sseJ pseudogene; but also to the acquisition of new functions. It has been reported that S. Typhi presents a pathogenicity island (named SPI-18) that harbours hlyE. The hlyE gene encodes a cytolysin that has proved to be cytotoxic toward different cell types [41–43]. SPI-18 is shared by other Salmonella enterica learn more serovars

that have been shown to cause systemic infections in humans, but is absent from S. Typhimurium [41]. In addition, the functional transfer of the S. Typhi hlyE gene to S. Typhimurium promotes deep organ infection in mice [41]. All this evidence suggests that S. Typhi has been selected for an increased cytotoxicity inside its host in order to perform a successful systemic infection. Thus, an increased cytotoxicity toward the epithelial barrier may guarantee the Methocarbamol development of a deeper infection and

a decreased retention inside epithelial cells at the bacterial entry point. On the other hand, the presence of the sseJ STM gene in S. Typhi significantly enhances the retention time within epithelial cells and/or the intracellular proliferation as we showed in Figure 6 in agreement with previous reports that indicate that SseJ enzymatic activity contributes to intracellular replication in host tissues [31, 38]. Accordingly, it is possible that the sseJ loss of function was selected in S. Typhi in order to promote a decreased retention/proliferation of bacteria inside the eukaryotic cells. It is known that the intracellular proliferation is essential for the virulence of S. Typhimurium [44]. Nevertheless, recent studies revealed that the magnitude of the CD8+ T cell response correlates directly to the intracellular proliferation in Salmonella enterica, showing that a reduced intracellular proliferation limits antigen presentation and development of a rapid CD8+ T cell response, indicating that reduced intracellular proliferation of virulent pathogens may be an important mechanism of immune evasion. [45].