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 initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. We found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wild-type CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, a phenylalanine deleted at residue 508 (delta508). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous deltaF508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than wild-type Cftr mice; no translocation occurred in deltaF508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound to S. typhi in the submucosa of Cftr wild-type mice than in deltaF508 heterozygous mice. We conclude that diminished levels of CFTR in heterozygotes may decrease susceptibility to typhoid fever.
Pier
G B
GB
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. gpier@channing.harvard.edu
Grout
M
M
Zaidi
T
T
Meluleni
G
G
Mueschenborn
S S
SS
Banting
G
G
Ratcliff
R
R
Evans
M J
MJ
Colledge
W H
WH
D000818:Animals; D002460:Cell Line; D003106:Colon / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004848:Epithelium / Q000382:microbiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology; D007422:Intestines / Q000382:microbiology* / Q000648:ultrastructure; D007583:Jejunum / Q000382:microbiology / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000382:microbiology; D009154:Mutation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D012485:Salmonella typhi / Q000472:pathogenicity / Q000502:physiology* / Q000648:ultrastructure; D012486:Salmonella typhimurium / Q000502:physiology; D014407:Tumor Cells, Cultured
C505032:CFTR protein, human; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator