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Salmonella typhi uses CFTR to enter intestinal epithelial cells

Nature volume 393, pages 79–82 (1998)Cite this article

Abstract

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 populations1. Here we investigate whether typhoid fever could be one such disease. The disease is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation2. 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 (Δ508). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous ΔF508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than wild-type Cftr mice; no translocation occurred in ΔF508 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 ΔF508 heterozygous mice. We conclude that diminished levels of CFTR in heterozygotes may decrease susceptibility to typhoid fever.

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Figure 1: Uptake of different Styphi and S. typhimurium strains by epithelial cells expressing mutant ΔF508 or wild-type CFTR.
Figure 2: Inhibition of uptake of Styphi Ty2 by T84 colonic epithelial cells with reagents specific to CFTR.
Figure 3: Styphi uses CFTR to translocate from the GI lumen to the submucosa.
Figure 4: Immunoelectron micrographs of Styphi Ty2 in the submucosal space of the GI tract of mice reacted with a monoclonal antibody to CFTR.

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Acknowledgements

We thank J. Olsen, J. Yankaskas and L. Johnson for CFT1 cells, A. Smith and colleagues (Genzyme) for C127 cell lines, P. Zeitlin for IB3 and C38 cells, C. Lee for advice on Salmonella uptake assays, and C. Lee and D. Kasper for reading the manuscript. This work was supported by the NIH, the Cystic Fibrosis Foundation and the Cystic Fibrosis Trust.

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Authors and Affiliations

  1. Department of Medicine, Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Gerald B. Pier, Martha Grout, Tanweer Zaidi, Gloria Meluleni & Simone S. Mueschenborn

  2. Department of Biochemistry and Biotechnology and Biological Sciences Research Council, Molecular Recognition Centre, University of Bristol, BS8 1TD, Bristol, UK

    George Banting

  3. Department of Physiology, University of Cambridge, Downing Street, CB2 3EG, Cambridge, UK

    Rosemary Ratcliff & William H. Colledge

  4. Wellcome/CRC Institute of Cancer and Developmental Biology and Department of Genetics, Tennis Court Road, University of Cambridge, CB2 1QR, Cambridge, UK

    Martin J. Evans

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  1. Gerald B. Pier
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Correspondence to Gerald B. Pier.

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Pier, G., Grout, M., Zaidi, T. et al. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393, 79–82 (1998). https://doi.org/10.1038/30006

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