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Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells

View ORCID ProfileDeepti Dabral, View ORCID ProfileHiren Ghosh, Masato Niwa, View ORCID ProfileTasuku Hirayama, Rinse de Boer, View ORCID ProfileMarjon de Vos, View ORCID ProfileGeert van den Bogaart
doi: https://doi.org/10.1101/2022.05.29.493834
Deepti Dabral
1Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands
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  • For correspondence: d.dabral@rug.nl
Hiren Ghosh
2Institute for Infection Prevention and Hospital Epidemiology, Medical Center, University of Freiburg, Germany
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Masato Niwa
3Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, 1–25–4, Daigaku-nishi, Gifu 201–1196, Japan
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Tasuku Hirayama
3Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, 1–25–4, Daigaku-nishi, Gifu 201–1196, Japan
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Rinse de Boer
1Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands
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Marjon de Vos
4GELIFES, University of Groningen, Groningen, Netherlands
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Geert van den Bogaart
1Department of Molecular Immunology and Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands
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Abstract

By far most urinary tract infections are caused by genetically diverse uropathogenic Escherichia coli (UPEC). Knowledge of the virulence mechanisms of UPEC is critical for drug development, but most studies focus on only a single strain of UPEC. In this study, we compared the virulence mechanisms of four antibiotic-resistant and highly pathogenic UPEC isolates in human blood monocyte-derived macrophages and a bladder epithelial cell (BEC) line: ST999, ST131, ST1981 and ST95. We found that while non-pathogenic E. coli strains are efficiently killed by macrophages in bactericidal single membrane vacuoles, the UPEC strains survive within double-membrane vacuoles. On side-by-side comparison, we found that whereas ST999 only carries Fe3+ importers, ST95 carries both Fe2+ and Fe3+ importers and the toxins haemolysin and colibactin. Moreover, we found that ST999 grows in the Fe3+ rich vacuoles of BECs and macrophages with concomitant increased expression of haem receptor chuA and the hydrogen peroxide sensor oxyR. In contrast, ST95 produces toxins in iron-depleted conditions similar to that of the urinary tract. Whereas ST95 also persist in the iron rich vacuoles of BECs, it produces colibactin in response to low Fe3+ contributing to macrophage death. Thus, iron regulates the contrasting toxicities of UPEC strains in macrophages and bladder epithelial cells due to low and high labile iron concentrations, respectively.

Key findings

  • Antibiotics resistant uropathogenic E. coli strains ST999, ST131, ST1981, and ST95 survive within spacious double membrane vacuoles. Non-pathogenic E. coli strains XL1 blue and MG1655 are cleared in single membrane vacuoles in macrophages.

  • ST999 lacks Fe2+ importer and toxins, and grows in iron rich vacuoles of macrophages and bladder epithelial cells.

  • ST95 carries both Fe2+ and Fe3+ importers and grows in iron low conditions.

  • ST95 expresses toxins and induces cell death of infected macrophages, but not of bladder epithelial cells.

  • Bladder epithelial cells have a higher pool of labile iron than macrophages. Differential expression of virulence factors by ST999 and ST95 in bladder epithelial cells and macrophages is dependent on iron concentration.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* g.van.den.bogaart{at}rug.nl

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 29, 2022.
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Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells
Deepti Dabral, Hiren Ghosh, Masato Niwa, Tasuku Hirayama, Rinse de Boer, Marjon de Vos, Geert van den Bogaart
bioRxiv 2022.05.29.493834; doi: https://doi.org/10.1101/2022.05.29.493834
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Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells
Deepti Dabral, Hiren Ghosh, Masato Niwa, Tasuku Hirayama, Rinse de Boer, Marjon de Vos, Geert van den Bogaart
bioRxiv 2022.05.29.493834; doi: https://doi.org/10.1101/2022.05.29.493834

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