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The coordinated action of a variety of virulence factors allows Salmonella enterica to invade epithelial cells and penetrate the mucosal barrier. Due to the lack of a suitable animal model, the molecular mechanisms of this process have been primarily studied in vitro using immortalized cell culture models. We have recently established a neonatal murine infection model that allows the analysis of both bacterial and host factors during the host-microbial interplay in vivo. Using this model, we demonstrate spontaneous intestinal colonization and Salmonella pathogenicity island (SPI)1-dependent mucosal translocation and spread to systemic organs following oral administration of Salmonella. Following invasion of enterocytes, intraepithelial proliferation and the formation of large intraepithelial microcolonies accompanied by Toll-like receptor (Tlr) 4 and 9-mediated immune stimulation is observed. Using quadruple, triple and single mutant bacteria in combination with complementation of individual SPI1 effector molecules we analyzed their contribution to enterocyte invasion, innate immune stimulation, microcolony formation and mucosal translocation in vivo. Together, our results characterize the critical role of individual bacterial effector molecules for the bacteria-enterocyte interaction during early infection in vivo.