Figure 2. The gastric innate immune response to Salmonella. (A) Following the invasion of the mucosa, the presence of Salmonella is detected by pattern recognition receptors. Extracellular Salmonella are detected by Toll-like receptors inducing a transcriptional response leading to the expression of pro- inflammatory cytokines such as IL-23. Intracellular Salmonella activate NOD-like receptors that can induce IL-23 expression, as well as the assembly of NLRC4/NLRP3 inflammasomes that activate Caspase-1, promoting the secretion of mature IL-1b and IL-18. SPI-1 mediated activation of Caspase-1 in epithelial cells might contribute to IL-18 secretion. (B) IL-18 and IL-23 amplify the inflammatory response by paracrine signaling. IL-18 induces the release peptides, and pro©mote the r2elease 0of C1XCch2emokineLsleaading ntoan dinflux eof nseutropBhils inito othe msucosca.(Ci)Inefiltranting nceutreophil.sare crucial for the of IFNc from T cells, while IL-23 induces the release of IL-22 and IL-17. These cytokines induce the increased production of mucins and antimicrobial killing of extracellular Salmonellae. Although considered an intracellular pathogen, Salmonella can be found extracellularly following transcytosis through M cells or after pyroptosis induced host cell lysis. Besides clearing the pathogen, neutrophil influx can also lead to damage to intestinal tissue, resulting in the loss of epithelial cell barrier function and promoting diarrhea. Do not distribute. vivo, lipocalin-2 is produced in response to S. typhimurium lipocalin-2.28 Indeed, Salmonella mutants lacking iroN fail to infections in the ileal mucosa of infected rhesus macaques. evade the scavaging effects of lipocalin-2 and are severely Expression of iNOS, calprotectin, MUC4, Duox2 and enteric attenuated for growth in the gut.21 β-defensins are all upregulated in the inflamed mucosa22-24 Detection of Salmonella by PRRs. Crossing the epithelial (Fig. 2). Since S. typhimurium infection of cultured colonic barrier allows Salmonella to escape the inhospitable environment epithelial cells does not induce the same response, it suggests that at the surface of the intestinal mucosa and to evade many paracrine IL-22 signaling is required. Consistently during antimicrobial defenses. However, once Salmonella has passed Citrobacter rodentium infections of mice, IL-22 is required for through M cells or enterocytes, it encounters the next layer of the expression of RegIIIc and Calprotectin.25 innate immune defenses, the monocyte-derived phagocytic cells In order to overcome the chemical barrier generated by these of the GALT: macrophages and dendritic cells. The main antimicrobial peptides, S. typhimurium has developed means to function of these cells is to remove invading microbes by phago- sense these host responses or effectors and to respond by cytosis and to alert other immune cells of the infection, either upregulating corresponding virulence mechanisms. For example, directly or by secreting pro-inflammatory cytokines. Following the PhoP-PhoQ two-component signal transduction system, phagocytosis, Salmonellae express their virulence-associated SPI-2 which Salmonella shares with many other bacteria, has been T3SS to establish themselves in an intracellular compartment shown to sense the presence of cationic antimicrobial peptides named the Salmonella containing vacuole (SCV).7 Within this as well as divalent cations and low pH.26 Activation of PhoQ compartment Salmonella can replicate to high numbers before induces a transcriptional program resulting in increased resistance exiting the cell and infecting new host cells. Although Salmonella against antimicrobial peptides that is achieved by modifications remains partially hidden within its intracellular niche, it cannot of lipid A either by acylation (PagP) or addition of an amino- completely escape host cell sensing. All monocytic cells express an arabinose moiety (Pmr system). Salmonellae lacking PhoP or array of germline-encoded pattern recognition receptors (PRR), PhoQ have been shown to be severely attenuated in an in vivo which enable them to detect pathogen-associated molecular model of infection and to confer partial protective immunity pattern molecules (PAMPs). Toll-like receptors (TLRs), which against subsequent wild-type Salmonella infections.27 Additional are located on the outer membrane of the cell (TLR1, 2, 4, 5, resistance mechanisms to innate defenses in the gut include 6, 10) or in intracellular vesicles (TLR3, 7, 8, 9, 11, 13 early and expression of enzymes encoded by the iroBCDE iroN locus, which late endosome, lysosomes), are the first PRRs to detect the alter the structure of the Salmonella Fe+ binding protein Ent, presence of Salmonella.29 TLRs can detect a variety of extracellular thereby preventing it from being bound and sequestered by and endosomal PAMPs such as LPS, bacterial lipoproteins, www.landesbioscience.com Gut Microbes 65