Cystic fibrosis (CF) is the most common autosomal recessive disease of the caucasian population and is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. The most common mutation—a deletion of phenylalanine at residue 508 (ΔF508)—is a trafficking defect where the CFTR becomes trapped in the endoplasmic reticulum. Pier et al.[1xSalmonella typhi uses CFTR to enter intestinal epithelial cells. Pier, G.B. et al. Nature. 1998; 393: 79–82Crossref | PubMed | Scopus (232)See all References][1]have now explored the question of why the incidence of CF is so high and have suggested that there is a selective advantage in being heterozygous for CFTR: resistance to gastrointestinal (GI) infection by Salmonella typhi. By testing epithelial cell lines expressing or not expressing wild-type CFTR, they have discovered that S. typhi, but not the related mouse pathogen Salmonella typhimurium, uses CFTR as the receptor for internalization. This difference in receptor utilization may explain, in part, the different hosts and symptoms of these bacteria. The levels of S. typhi translocated from the GI lumen to the submucosa in wild-type mice, mice heterozygous for the ΔF508 allele of murine CFTR, and mice homozygous for the ΔF508 allele were measured. Compared with the wild-type mice, 86% less bacteria were detected in heterozygous mice and virtually none were found in the homozygous CF mice. Moreover, quantitative electron microscopy using antibodies to CFTR revealed that, after infection with S. typhi, submucosal tissue from heterozygous mice showed lower levels of CFTR than did tissue from wild-type mice, correlating with the reduced translocation of S. typhi. These results suggest that decreased expression of CFTR in people heterozygous for ΔF508 CFTR may increase resistance to typhoid fever, favoring maintenance of this mutation in the population.