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Cyclic AMP–regulated exocytosis of Escherichia coli from infected bladder epithelial cells

Nature Medicine volume 13, pages 625–630 (2007)Cite this article

Abstract

The superficial bladder epithelium is a powerful barrier to urine and also serves as a regulator of bladder volume, which is achieved by apical exocytosis of specialized fusiform vesicles during distension of the bladder. We report that type 1 fimbriated uropathogenic Escherichia coli (UPEC) circumvents the bladder barrier by harboring in these Rab27b/CD63-positive and cAMP-regulatable fusiform vesicles within bladder epithelial cells (BECs). Incorporation of UPEC into BEC fusiform compartments enabled bacteria to escape elimination during voiding and to re-emerge in the urine as the bladder distended. Notably, treatment of UPEC-infected mice with a drug that increases intracellular cAMP and induces exocytosis of fusiform vesicles reduced the number of intracellular E. coli.

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Figure 1: Uropathogenic E. coli invade superficial BECs through fusiform canals.
Figure 2: E. coli entry into Rab27b+ vesicles within BECs.
Figure 3: E. coli exocytosis from infected BECs.
Figure 4: Forskolin treatment causes exocytosis of fusiform vesicles in BECs and reduces UTI.

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Acknowledgements

We thank A. Aballay (Department of Molecular Genetics and Microbiology, Duke University Medical Center) for the gift of the S. enterica SL1344 and M. Kuehn (Department of Biochemistry, Duke University Medical Center) for the pKEN-HcRed plasmid; W. Fennell and H. Estrada for their help with electron microscopy; A. Aballay, R. Valdivia and M. Kuehn for helpful discussion; C. Shelburne and C. Kunder for their critical reading of the manuscript. This work was supported by US National Institutes of Health grants R01 AI-35678, R37DK50814 and R21 AI056101.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Brian L Bishop, Mathew J Duncan, Jeongmin Song & Soman N Abraham

  2. Department of Pathology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Guojie Li & Soman N Abraham

  3. Division of Pulmonary, Department of Medicine, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, 27710, North Carolina, USA

    David Zaas

  4. Department of Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Soman N Abraham

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Contributions

B.L.B. performed the experiments in this work. G.L. produced the GFP-Rab27b–expressing 5637 BECs and the Rab27b knockdown 5637 BECs. J.S. performed the IL-6 ELISA. M.J.D. initiated the laboratory use of the in vitro model of E. coli infection of 5637 BECs. B.L.B, D.Z and S.A. wrote the paper; the other authors read and commented on the manuscript.

Corresponding authors

Correspondence to Brian L Bishop or Soman N Abraham.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

E. coli interact with secretory lysosomes of 5637 BECs in vitro. (PDF 387 kb)

Supplementary Fig. 2

E. coli enters BECs through CD63+ vesicles and bypasses the classical endocytic pathway. (PDF 1055 kb)

Supplementary Fig. 3

Loss of intracellular E. coli is not due to BEC lysis or bacterial degradation. (PDF 247 kb)

Supplementary Methods (PDF 79 kb)

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Bishop, B., Duncan, M., Song, J. et al. Cyclic AMP–regulated exocytosis of Escherichia coli from infected bladder epithelial cells. Nat Med 13, 625–630 (2007). https://doi.org/10.1038/nm1572

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