Project: Bacterial and host factors governing enterocyte egress of SalmonellaCopyright: © Hornef
The intestinal epithelium represents the port of entry for a number of important human enteropathogens such as Salmonella. The ability to induce internalization by non-phagocytic enterocytes is facilitated by the Salmonella pathogenicity island (SPI)1 encoded type 3 secretion system (T3SS) and a number of effector molecules. Upon internalization, Salmonella employs additional SPI2-T3SS effectors to evade the cellular antimicrobial host defense and generate a replicative endosomal niche. This interaction with the host epithelium represents a hallmark of Salmonella pathogenesis and bacterial and host factors involved in this process have been extensively studied.
However, few studies have addressed the underlying mechanism and contributing factors governing egress of Salmonella from infected enterocytes. Egress at the basolateral site is required to overcome the intestinal epithelial barrier and allow systemic infection. Alternatively, egress at the apical site might promote luminal colonization and host transmission. We have recently developed an in vivo infection model that allows visualization of Salmonella infected enterocytes and observed a transcytosis arrest of SPI2 T3SS mutant Salmonella SCVs suggesting a critical role of the SPI2 T3SS and several translocated effector molecules in the microtubule-mediated transport of the SCV through the epithelial barrier in vivo. Additionally, an in vitro assay that facilitates quantitative analysis of the bacterial and host factors involved in bacterial egress has been established.
The present research proposal aims at the characterization of the process of bacterial egress from infected enterocytes, the identification of host and bacterial factors involved in this process and the analysis of apical enterocyte egress and its role for host transmission. The results are expected to improve our understanding of this initial step of the Salmonella pathogenesis and thereby identify therapeutic targets that act early during the course of the infection.