Salmonella Gut Invasion Involves TTSS-2-Dependent Epithelial Traversal, Basolateral Exit, and Uptake by Epithelium-Sampling Lamina Propria Phagocytes

Salmonella Typhimurium causes diarrhea by infecting the epithelium and lamina propria of the intestinal mucosa and by secreting various effector proteins through type ill secretion systems (TTSSs). However, the mechanisms by which Salmonella transverses the epithelium and is subsequently released into the lamina propria are poorly understood. Using a murine Salmonella-diarrhea model and in vivo microscopy, we show that epithelial traversal requires TTSS-1-mediated invasion and TTSS-2-dependent trafficking to the basolateral side. After being released into the lamina propria, the bacterium is transiently extracellular before being taken up by phagocytes, including CD11c(+)CX(3)CR1(high) monocytic phagocytes (MPs), which were found to constitutively sample cellular material shed from the basolateral side of the epithelium. Thus, Salmonella infects the cecal mucsa through a step-wise process wherein the bacterium transverses the epithelium through TTSS-2-dependent trafficking and then likely exploits lamina propria MPs, which are sampling the epithelium, to enter and replicate within the host.