SALMONELLA-TYPHI USES CFTR TO ENTER INTESTINAL EPITHELIAL-CELLS

Homozygous mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF). In the heterozygous state , increased resistance to infectious diseases may maintain mutant CFTR alleles at high levels in selected populations'. Here we investigate whether typhoid fever could be one such disease. The disease is initia ted when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation(2). We found that S, typhi but not the relat ed murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wild-type CFTR internalized more S. typhi tha n isogenic cells expressing the most common CFTR mutation, a phenylala nine deleted at residue 508 (Delta 508). Monoclonal antibodies and syn thetic peptides containing a sequence corresponding to the first predi cted extracellular domain of CFTR inhibited uptake of S. typhi. Hetero zygous Delta F508 Cftr mice translocated 86% fewer S. typhi into the g astrointestinal submucosa than wild-type Cftr mice; no translocation o ccurred in Delta F508 Cftr homozygous mice. The Cftr genotype had no e ffect on the translocation of S. typhimurium. Immunoelectron microscop y revealed that more CFTR bound to S. typhi in the submucosa of Cftr w ild-type mice than in Delta F508 heterozygous mice. We conclude that d iminished levels of CFTR in heterozygotes may decrease susceptibility to typhoid fever.