Typhimurium that lack certain SPI-1-encoded effector proteins, or that are unable to display the SPI-1 T3SS on their surfaces, are unable to invade M cells and are avirulent by the oral route (Ellermeier et al., 2005;Galan, 2001;Jones et al., 1994). epithelium is usually highly vulnerable to microbial attack. Indeed, infections acquired through the consumption of contaminated food and water are a leading cause of morbidity and mortality worldwide. Children under the age of 5, in developing countries, are especially susceptible to such infectious caused by rotavirus (Franco et al., 2006),Shigellaspecies (Levine et al., 2007), andSalmonella enterica(Petri et al., 2008). Infections caused byS. entericaserovar Typhi (S. Typhi) alone are estimated to cause more than 16 million cases of typhoid fever, and more than half a million deaths, each year (Levine, 2006). In developed countries such as the United States,Escherichia coliO157:H7 andS. entericaserovar Typhimurium (S. Typhimurium) infections are increasingly associated with food processing and handling, and they therefore represent an emerging public health threat (Maki, 2009). In 2009 2009, for example, an outbreak ofS. Typhimurium associated with contaminated peanut butter affected hundreds of persons and resulted in at least 8 deaths. Additionally, many enteric pathogens including S. Typhimurium, as well as bacterium- and plant-derived toxins, are considered by the Centers for Disease Control and Prevention (CDC) as bioterrorism brokers that AV412 could be (or have already been) deliberately used to contaminate food and water supplies with the intent of inducing illness at a local, regional or national level (Mantis et al., in press). The intestinal epithelium is equipped with a number of innate defense mechanisms, to deter microbial pathogens and toxins from gaining access to epithelial cells receptors (Mantis and Bry, 2008;Turner, 2009). First, the epithelium itself is a barrier, consisting of a single Goat polyclonal to IgG (H+L)(HRPO) layer of columnar epithelial cells arranged side-by-side and joined at their apical aspects by tight junctions. In the small intestine, absorptive enterocytes are the predominant epithelial cell type, and are responsible for the bulk of nutrient absorption from the gut lumen. The apical surfaces of these cells consist of rigid, closely packed microvilli rich in membrane-bound glycolipids and stalked glycoproteins, some of which are known receptors for pathogens (e.g., rotavirus) and toxins (e.g., cholera toxin, or CT). The tips of these microvilli are coated with a 400500 nm thick glycoprotein meshwork known as the filamentous brush border glycocalyx (FBBG), which is proposed to function in epithelial defense by limiting the access of virus- and bacterium-sized particles to membrane-bound receptors (Frey et al., 1996;Mantis et al., 2000). Second, interspersed with the adsorptive enterocytes are a number specialized epithelial cell types that assist in innate immunity, including mucin-producing goblet cells and AV412 crypt-situated Paneth cells, which produce antimicrobial compounds including lysozyme and alpha-defensins (Deplancke and Gaskins, 2001;Lievin-Le Moal and Servin, 2006;Ouellette, 2006). Finally, epithelial cells, upon infection or toxin exposure, call for help by secreting pro-inflammatory chemokines and lipid mediators that trigger the recruitment and activation of leukocytes (e.g., polymorphonuclear cells) that aid in the phagocytosis of extracellular pathogens (Tam et al., 2008). However, the innate immune system is of only limited efficacy in deterring the most virulent pathogens and toxins.S. Typhimurium, for example, defends itself against antimicrobial compounds in the intestinal lumen by altering its own gene expression, reducing permeability of its outer membrane, and activating extracellular scavenging pathways (Bader et al., 2003;Haraga et al., 2008;Raffatellu et al., 2009). Certain enterotoxins, of both plant and microbial origins, are so potent that even a small number of molecules are sufficient to induce epithelial dysfunction and/or host cell death AV412 (Mantis, 2005;Matsumura et al., 2007). Immunity against these agents necessitates the involvement of the bodys adaptive immune system, specifically the gut-associated lymphoid tissues (GALT). In the small intestine, the GALT consists of aggregates of lymphoid follicles known as Peyers patches (Fig. 1). These organized lymphoid follicles contain germinal centers enriched in B cells whose differentiation and somatic cell hypermutation are driven in response to antigens present AV412 in the intestinal lumen (Brandtzaeg and Johansen, 2005;Cerutti and Rescigno, 2008;Suzuki and Fagarasan, 2009). By virtue of the local cytokine environment, B cells within the Peyers patches not only undergo class switch recombination preferentially to IgA, but they also express J chain, the 15 kDa protein that serves to promote immunoglobulin dimerization (Brandtzaeg, 1974;Brandtzaeg and Johansen, 2005). As a result, mucosa-derived plasma cells secrete IgA in a dimeric or polymeric form. == Figure 1. SIgA: Induction, transport and function in the intestinal lumen. == Particulate antigens (e.g., pathogens and toxins) present in the.