disease in humans and in animal hosts. Salmonellae are taken up vacuolar compartment in the cytoplasm.7 Crucial for this intra- via contaminated food and can infect a broad range of hosts; cellular phase is a second type 3 secretion system encoded by certain host-adapted serovars can even cause a severe systemic Salmonella pathogenicity Island 2 (SPI-2). While non-typhoidal disease. For example, the human restricted S. enterica serovar strains remain restricted to the GI tract, typhoidal Salmonella Typhi causes Typhoid fever, which affects over 20 million people serovars then disseminate from the GI tract to mesenteric lymph worldwide and leads to approximately 200,000 deaths per year. nodes and colonize systemic sites, like the liver and spleen. In contrast, S. enterica serovar Typhimurium (S. typhimurium) causes a self-limiting gastroenteritis in humans, while mice Innate Immune Response to Salmonella infected with this serovar get a systemic disease with a patho- genesis resembling typhoid fever in humans. Thus murine Salmonella is a very successful enteric pathogen because it has infections with S. typhimurium are studied as a model for human developed strategies to cope with most of the immune defenses Typhoid infections. Interestingly the disease outcome varies employed by the host during the different phases of the disease. significantly between different inbred mouse strains. C57BL/6 In the following we will describe in detail the innate immune mice get an acute infection leading to death within 6–8 d post- mechanisms employed by the host and how Salmonella reacts to infection; 129Sv mice contain the infection and can become and subverts these immune responses. persistently infected,4 which is reminiscent of S. typhi infections. Gastric innate immune mechanisms. One of the first obstacles Humans with Typhoid can become persistently infected once the faced by Salmonella is a thick layer of mucous that covers the initial acute phase has subsided, and this population serves as a surface of the gut epithelium and provides an initial barrier, significant reservoir for disease transmission. which must be penetrated in order to gain direct contact with the After being ingested with contaminated food, Salmonellae epithelium. This mucus layer is formed by mucins, a family of reach the gut lumen where they have to compete with the resident glycoproteins secreted by specialized types of epithelial cells, intestinal microbiota for nutrients. Colonization resistance is called Goblet cells (Fig. 1). In addition to the mucins, cells in provided by the © indigenous 2 co0mme1nsals 2 and is Lan and important butethe s gastrointestinal Bio stracctsecrete ience several types.of antimicrobial often overlooked barrier to infection with enteric pathogens. peptides, which are small amphipathic proteins that function like Treatment with an antibiotic such as streptomycin before the peptide antibiotics by disrupting the integrity of the bacterial cell infection has been shown to reduce the infectious dose of membrane. The production and release of antimicrobial peptides S. commonly typhimurium used in in some mice mouse by . mDodelosof 100,000-fold Sanlmonoella and is tinfecdtioni therefore sbarrtierragiainbstmuicrobtial and mucins by the epithelial einv.asion cells and of the an gut important represents part a of major the to circumvent colonization resistance.5 Importantly, several innate immune response. While some antimicrobial peptides groups have demonstrated that S. typhimurium uses its virulence are expressed constitutively, many are induced as part of the factors to induce intestinal inflammation during the intestinal inflammatory response to invading pathogens.15 Paneth cells of phase to gain a growth advantage over the microbiota. For the intestinal crypts are the most abundant producers of con- example, reactive oxygen species generated during inflammation stitutively expressed antimicrobial peptides in mammals, such as react with endogenous, luminal sulfur compounds (thiosulphate) a- and β-defensins (cryptdins in mice), CRS peptides, lysozyme to form a new respiratory electron acceptor, tetrathionate, which and phospholipase A2 (sPLA2).16 They can be induced to secrete S. typhimurium has evolved to use, while commensals lack the additional types of antimicrobial peptides, such as cathelicidins, required metabolic pathways.6 angiogenin 4 (ANG4) and the C-type lectins RegIIIβ/c15, in There are two main components to Salmonella infections in response to microbial PAMPs. In addition to Paneth cells, the intestine: adherence and subsequent invasion.7 Several epithelial cells are also known to produce inducible antimicrobial adhesins and fimbriae are necessary to mediate adherence to peptides such as RELM-b, RegIIIc, calprotectin and β-defensins. epithelial cells in the gut.8 Following adherence, Salmonella During S. typhimurium infections of Streptomycin-pretreated can use several different mechanisms to cross the intestinal mice, RegIIIβ and RegIIIc expression is markedly increased.17 epithelium. (Fig. 1.) A major route of entry is through M cells in RegIIIc secretion contributes to the clearance of other intestinal the FAE overlying PPs, which transport antigens and bacteria pathogens such as Listeria monocytogenes and Enterococcus spp.18 from the lumen to the lamina propria.9 Salmonella can also However, unlike these pathogens Salmonella is better adapted to induce its internalization in non-phagocytic enterocytes through counter host defenses and might even profit from increased its virulence-associated type 3 secretion system encoded by production of C-type lectins to gain a growth advantage over Salmonella pathogenicity Island 1 (SPI-1).10 Invasion also has the microbiota. In vitro, RegIIIβ kills diverse commensal gut been proposed to occur by paracellular pathways following bacteria but not Salmonella, which can be attributed to its specific disruption of tight junctions11 or via CX3CR1+ macrophages/ cell envelope structure.19 RegIIIc production is absent in mice DCs, which intercalate between epithelial cells.12-14 However, the deficient for MyD88, an adaptor of TLR signaling.20 In addition importance of these invasion-independent alternative pathways to TLRs, cytokines of the IL-23/IL-22 axis (see below) might remains to be determined. also be involved in the production of antimicrobial peptides After crossing the intestinal barrier at the site of PPs, the (Fig. 2). In vitro, IL-22 is known to induce the expression of bacteria are taken up by phagocytic immune cells like macro- inducible Nitric Oxide Synthase (iNOS), the mucin MUC4 and phages. Once phagocytosed, Salmonellae replicate within a the siderophore lipocalin-2 in human colonic epithelial cells.21 In 64 Gut Microbes Volume 3 Issue 2