Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis

Authors

  • Keira Melican,

    1. Departments of Neuroscience and
    2. Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, S-171 77, Sweden.
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  • Jorrit Boekel,

    1. Departments of Neuroscience and
    2. Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, S-171 77, Sweden.
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  • Lisa E. Månsson,

    1. Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, S-171 77, Sweden.
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    • Present address: Division of Gastroenterology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.

  • Ruben M. Sandoval,

    1. Division of Nephrology, Department of Medicine, Indiana Center for Biological Microscopy, Indianapolis, IN 46202, USA.
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  • George A. Tanner,

    1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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  • Örjan Källskog,

    1. Department of Medical Cell Biology, Uppsala University, Uppsala, S- 751 23, Sweden.
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  • Fredrik Palm,

    1. Department of Medical Cell Biology, Uppsala University, Uppsala, S- 751 23, Sweden.
    2. Department of Medicine, Division of Nephrology and Hypertension, Georgetown University, Washington, DC 20007, USA.
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  • Bruce A. Molitoris,

    1. Division of Nephrology, Department of Medicine, Indiana Center for Biological Microscopy, Indianapolis, IN 46202, USA.
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  • Agneta Richter-Dahlfors

    Corresponding author
    1. Departments of Neuroscience and
    2. Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, S-171 77, Sweden.
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*E-mail agneta.richter.dahlfors@ki.se; Tel. (+46) 8 52487425; Fax (+46) 8 333864.

Summary

Ascending urinary tract infections can cause extensive damage to kidney structure and function. We have used a number of advanced techniques including multiphoton microscopy to investigate the crucial early phases of uropathogenic Escherichia coli induced pyelonephritis within a living animal. Our results reveal a previously undescribed innate vascular response to mucosal infection, allowing isolation and eradication of the pathogen. The extremely rapid host response to mucosal infection was highlighted by the triggering of a cascade of events within 3–4 h. Epithelial signalling produced an increase in cellular O2 consumption and affected microvascular flow by clotting, causing localized ischaemia. Subsequent ischaemic damage affected pathophysiology with actin re-arrangement and epithelial sloughing leading to paracellular bacterial movement. A denuded tubular basement membrane is shown to hinder immediate dissemination of bacteria, giving the host time to isolate the infection by clotting. Suppression of clotting by heparin treatment caused fatal urosepsis. Clinically these findings may be relevant in antibiotics delivery in pyelonephritis patients and to the use of anticoagulants in sepsis.

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