**2.2 Intestinal phase: invasion and intracellular survival**

Shortly after adhesion to a host cell, *Salmonella* invasion proceeds as a consequence of the activation of host cell signaling pathways leading to profound cytoskeletal rearrangements [56]. These internal modifications dislocate the normal epithelial brush border and induce the subsequent formation of membrane ruffles that engulf adherent bacteria in barge vesicles called *Salmonella* containing vacuoles (SCVs), which is the only intracellular compartment where *Salmonella* cells survive and replicate [57, 58]. Simultaneously, induction of secretory response in the intestinal epithelium initiates recruitment and transmigration of phagocytes from the submucosal space into the intestinal lumen. Alternatively, *Salmonella* cells may be directly engulfed by dendritic cells from the submucosa. Taken up During SCV maturation, *Salmonella* induces *de novo* formation of an F-actin meshwork around bacterial vacuoles, a process which is termed vacuole-associated action polymerization (VAP) and is important for maintenance of the integrity of the vacuole membrane [59]. Furthermore, intracellular *Salmonella* can induce the formation of long filamentous membrane structure called *Salmonella*-induced filaments (SIFs) [60], which may lead to an increased availability of nutrients within the SCV [61]. A fraction of SCVs transcytose to the basolateral membrane. Once across the intestinal epithelium, *Salmonella* are engulfed by phagocytes and internalized again with SCVs, triggering a response similar to that reported inside epithelial and M cells to ensure bacterial survival and replication [62]. The pathogenic bacterium must at this stage employ many virulence strategies to evade the host defense mechanisms (**Figure 1**).

The majority of the virulence determinants are located within highly conserved SPIs on the chromosome, while others are either on a virulence plasmid (pSLT) or elsewhere in the chromosome. To date, 21 SPIs have been identified in *Salmonella*, and the generalist *S. typhimurium* and the invasive *S. typhi* genomes share 11 (SPIs-1 to 6, 9, 11, 12, 13 and 16). Two SPIs namely SPI-8 and 10 were initially found in *S. typhi* and without counterparts in *S. typhimurium* chromosome; SPI-14 is specific to *S*. *typhimurium*, while *SPIs*-7, 15, 17 and 18 are specific to *S. typhi*; and SPIs-19, 20 and 21 are absent in both of them [63]. Because of the prominence of the SPIs in pathogenesis, the virulence factors encoded on the major SPIs, SPI-1 to SPI-5 are described below, and their respective functions summarized (**Tables 2** and **3**).
