Fig. 12.16 Salmonella enterica serovar Typhimurium is an important cause of food poisoning and penetrates the epithelial layer in three ways. Salmonella
If defenses fail, salmonellae can enter the bloodstream and cause a systemic infection neutrophil caspase 1 activation IL-18 CXCL8 IL-1˜Chemokines and cytokines produced by macrophages recruit neutrophils out of blood vessels and activate them Dendritic cells loaded with bacterial antigens acquired directly or from macrophages travel to the mesenteric lymph node via afferent lymphatics and provoke an adaptive immune response Salmonellae enter and kill M cells, and then infect macrophages and epithelial cells Salmonellae invade the luminal surface of epithelial cells Salmonellae enter phagocytic cells that are sampling the gut luminal contents M cell TLR-5 gut lumen these cells form a barrier that is normally impermeable to macromolecules and invaders. The constant production of new epithelial cells from stem cells in the crypts also allows the barrier to be repaired rapidly after mechanical damage or loss of cells. Nonetheless, pathogens have acquired mechanisms to gain entry through these barriers; some entry mechanisms used by salmonella are shown in Fig. 12.16, and those used by shigella in Fig. 12.17.
Epithelial cells also bear TLRs on both their apical and basal surfaces, from which they can sense bacteria in the gut lumen and those that have penetrated across the epithelium. In addition, epithelial cells carry TLRs in intracellular vacuoles that can detect intracellular pathogens or extracellular pathogens and their products that have been internalized by endocytosis. Epithelial cells also have intracellular sensors, described in Chapter 3, and can react when microorganisms or their products enter the cytoplasm. These sensors include the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 (see Section 3-8 and Fig. 3.17). NOD1 recognizes a diaminopimelic acid-containing peptide that is found only in the cell walls of Gram-negative bacteria. NOD2 recognizes a muramyl dipeptide found in the peptidoglycans of most bacteria, and epithelial cells defective in NOD2 are less resistant to infection by intracellular bacteria. Mice lacking NOD2 also show increased translocation of bacteria across the epithelium and out of Peyer’s patches. A defect in recognition of the commensal microbiota by NOD2 also seems to be important in Crohn’s disease, as up to 25% of patients carry a mutation in the NOD2 gene that renders the NOD2 protein nonfunctional.
Shigella cell-wall peptides bind and oligomerize NOD1, activating the NF˜B pathway RIPK2 I˜K I˜B NF˜B NOD1
Ligation of TLRs or NOD proteins in epithelial cells stimulates the production of cytokines, such as IL-1 and IL-6, and the production of chemokines. The chemokines include CXCL8, which is a potent neutrophil chemoattractant, and CCL2, CCL3, CCL4, and CCL5, which attract monocytes, eosinophils, and T cells out of the blood. Stimulated epithelial cells also increase their production of the chemokine CCL20, which attracts immature dendritic cells toward the epithelial surface (see Sections 12-4 and 12-7).