The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an epithelial receptor mediating the translocation of Salmonella enterica serovar Typhi to the gastric submucosa. Since the level of cell surface CFTR is directly related to the efficiency of serovar Typhi translocation, the goal of this study was to measure CFTR expression by the intestinal epithelium during infection. CFTR protein initially present in the epithelial cell cytoplasm was rapidly trafficked to the plasma membrane following exposure to live serovar Typhi or bacterial extracts. CFTR-dependent bacterial uptake by epithelial cells increased (>100-fold) following CFTR redistribution. The bacterial factor which triggers CFTR redistribution is heat and protease sensitive. These data suggest that serovar Typhi induces intestinal epithelial cells to increase membrane CFTR levels, leading to enhanced bacterial ingestion and submucosal translocation. This could be a key, early step in the infectious process leading to typhoid fever.Salmonella enterica serovar Typhi causes typhoid or enteric fever and initiates infection by entering the enterocytes and specialized M cells of the small intestine, after which the bacterium is translocated to the intestinal submucosa and ingested by host macrophages. The mechanism by which serovar Typhi enters enterocytes is complex and involves intercellular adhesins (5) and intracellular signaling components (18) which modify the host cell cytoskeletal (6) and vacuolar (7) organization. This process is initiated when adhesins and signaling components are delivered into the host cell by the bacterium via the bacterial type III secretion apparatus (4). Since assembly of the type III secretion apparatus is stimulated by bacterium-epithelial cell contact (9), early interactions between serovar Typhi and the epithelial cell play an important role in the initiation of infection.