Salmonella enterica Serovar Typhi Modulates Cell Surface Expression of Its Receptor, the Cystic Fibrosis Transmembrane Conductance Regulator, on the Intestinal Epithelium

Abstract

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.

The interaction of gut microbes with host ABC transporters

“…48 Of particular note, during serovar S. typhi infection of enterocytes the cell surface expression of the CFTR protein by intestinal epithelium was found to be markedly increased. 49 This increase results from the redistribution of pre-formed CFTR protein from intracellular stores to the epithelial cell plasma membrane, and the increased membrane expression of CFTR is correlated with enhanced CFTR-dependent entry of S. typhi into epithelial cells. 49 It was also determined that the products of certain strains of bacteria representing the intestinal microflora are also able to trigger CFTR in epithelial cells.…”

“…49 This increase results from the redistribution of pre-formed CFTR protein from intracellular stores to the epithelial cell plasma membrane, and the increased membrane expression of CFTR is correlated with enhanced CFTR-dependent entry of S. typhi into epithelial cells. 49 It was also determined that the products of certain strains of bacteria representing the intestinal microflora are also able to trigger CFTR in epithelial cells. 50 Such data provide compelling evidence to suggest that commensal microorganisms present in the intestinal lumen can affect the efficiency of S. typhi invasion of the intestinal submucosa and as a consequence, could be a key determinant influencing host susceptibility to typhoid fever.…”

“…45,46 Markedly increased surface expression during S. typhi infection, due to redistribution of CFTR from intracellular stores to the epithelial cell membrane. 49 …”

Commensal Bacteria Increase Invasion of Intestinal Epithelium bySalmonella entericaSerovar Typhi

“…Cell surface expression of the CFTR protein by intestinal epithelium is increased during serovar Typhi infection (12). This increase is brought about by a redistribution of preformed CFTR protein from intracellular stores to the epithelial cell plasma membrane.…”

Rate of Inversion of the Salmonella enterica Shufflon Regulates Expression of Invertible DNA

“…The type IVB structural pilin, PilS, binds to the cystic fibrosis transmembrane conductance regulator, the recognized eukaryotic cell receptor for serovar Typhi (9,16,19).…”