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The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection

Abstract

The urinary tract functions in close proximity to the outside environment, yet must remain free of microbial colonization to avoid disease. The mechanisms for establishing an antimicrobial barrier in this area are not completely understood. Here, we describe the production and function of the cathelicidin antimicrobial peptides LL-37, its precursor hCAP-18 and its ortholog CRAMP in epithelial cells of human and mouse urinary tract, respectively. Bacterial contact with epithelial cells resulted in rapid production and secretion of the respective peptides, and in humans LL-37/hCAP-18 was released into urine. Epithelium-derived cathelicidin substantially contributed to the protection of the urinary tract against infection, as shown using CRAMP-deficient and neutrophil-depleted mice. In addition, clinical E. coli strains that were more resistant to LL-37 caused more severe urinary tract infections than did susceptible strains. Thus, cathelicidin seems to be a key factor in mucosal immunity of the urinary tract.

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Figure 1: Immunohistochemical staining of sections from healthy human renal cortical tissue (ad), a piece of human renal cortex incubated in cell culture medium for 24 h (e,f), and a piece infected with uropathogenic E. coli for the same time (g,h).
Figure 2: Cathelicidin LL-37/hCAP-18 in vitro.
Figure 3: Immunofluorescent staining of two sections (one section is shown in ad and the other is shown in eh) from the renal cortex of a NMRI mouse at 24 h of pyelonephritis.
Figure 4: Relevance of epithelium-derived cathelicidin for the protection of the urinary tract against infection.
Figure 5: The course of experimental urinary tract infection in CRAMP-producing Camp+/+ and CRAMP-deficient Camp−/− mice.
Figure 6: Sensitivity of uropathogenic E. coli to synthetic LL-37 peptide expressed as a minimal inhibitory concentration (MIC) of LL-37.

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Acknowledgements

We thank Z. Fehervízyová and T. Baltesová for help collecting urine samples, M. Lindh for technical assistance and G. Kronvall for help with single-strain regression analysis. This work was supported by ALF Project Funding, The Swedish Society of Medicine, The Swedish Association of Kidney Patients, funds from the Karolinska Institute, Magn. Bergvalls Foundation, Capio Foundation, The Swedish Research Council (04X-2887, 06X-11217), The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), and the Knut and Alice Wallenberg Foundation.

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Correspondence to Annelie Brauner.

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Supplementary information

Supplementary Fig. 1

LL-37/hCAP-18 levels in urine of 28 healthy children and in 29 children with acute urinary tract infection. (PDF 77 kb)

Supplementary Fig. 2

Human LL-37/hCAP-18 mRNA and protein levels in noninfected renal and uroepithelial cells and tissues. (PDF 27 kb)

Supplementary Methods (PDF 71 kb)

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Chromek, M., Slamová, Z., Bergman, P. et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med 12, 636–641 (2006). https://doi.org/10.1038/nm1407

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