REVIEW © 2012 Landes Bioscience. Do not distribute. Figure 1. Schematic representation showing the different routes Salmonella can take in order to invade the intestinal mucosa. (1) The major pathway of invasion is through M cell mediated transcytosis at the Peyer’s patches. (2) An alternative route is via uptake by enterocytes. (3) This route requires the injection of bacterial effector proteins by the SPI-1 Type 3 Secretion System that induce ruffling and uptake of the bacterium. Uptake through intercalating CX3CR1+ macrophages/DCs might represent an additional route of invasion. pathogens, but also normally prevents the innate immune system from encountering commensal-derived antigens. Each epithelial cell maintains intimate association with its neighbors and seals the surface of the gut with tight junctions. Non-hematopoietic cells in the epithelial layer help to maintain this barrier by secreting mucus (goblet cells) or antimicrobial peptides (Paneth cells) (Fig. 1). Underlying this epithelial cell layer is the lamina propria, which contains a highly organized lymphoid tissue commonly referred to as gut-associated lymphoid tissue (GALT). The GALT is comprised of isolated and aggregated lymphoid follicles and is populated by a wide array of lymphocytes, such as T cells and B cells, dendritic cells, macrophages and neutrophils (Fig. 1). These cells regulate inflammatory responses to bacteria and antigens that breach the gastrointestinal barrier, protect the mucosa against harmful pathogens, and scavenge dead cells and foreign debris. Aggregated lymphoid follicles, so-called Peyer’s patches (PP), are surrounded by a particular epithelium, the follicle-associated epithelium (FAE), which forms the interface between the GALT and the luminal microenvironment. The PPs have an important role in the immune surveillance of the intestinal lumen and facilitate the induction of defense against pathogens or immune tolerance (oral tolerance) as a result of the complex interplay between immune cells located in the lymphoid follicles and the FAE. The FAE contains specialized cells named M (for micro- fold) cells, which transport luminal antigens and bacteria to the basolateral side by transcytosis. At their basal surface, the cell membrane of M cells is extensively folded around underlying lymphocytes and antigen-presenting cells that activate or inhibit the immune response leading to either tolerance or systemic immune responses. In addition, antigen-presenting dendritic cells (DCs) send processes between intestinal epithelial cells without disturbing tight junction integrity and sample antigens from commensal and pathogenic gut bacteria. B cells and memory cells get activated by antigen-presenting cells in PPs and then travel to the mesenteric lymph nodes (MLN), where the immune response is amplified. Thus the GALT plays a crucial part in the interplay between the innate and adaptive immune system. Salmonella Infections Salmonella enterica is a flagellated, Gram-negative, facultative intracellular bacterial species that is a leading cause of enteric www.landesbioscience.com Gut Microbes 63