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Human neutrophil peptides 1-3 protect the murine urinary tract from uropathogenic Escherichia coli challenge

Jorge J Canas1,2, Dong Liang1, Vijay Saxena1

  • 1Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202.

Proceedings of the National Academy of Sciences of the United States of America
|September 26, 2022
PubMed

Insights

Human alpha-defensins 1-3 protect the urinary tract from infection. Transgenic mice expressing these antimicrobial peptides show protection against uropathogenic Escherichia coli, suggesting a therapeutic target for urinary tract infections.

Area of Science:

  • Immunology
  • Microbiology
  • Genetics

Background:

  • Antimicrobial peptides (AMPs) are crucial for host defense against pathogens.
  • Alpha-defensins 1-3 (DEFA1A3) are AMPs found in human kidney collecting ducts, with locus variations linked to urinary tract infection (UTI) risk.
  • DEFA1A3 is not naturally expressed in mice, necessitating a transgenic model.

Purpose of the Study:

  • To investigate the biological role of the DEFA1A3 locus in the murine urinary tract.
  • To evaluate the protective effects of human DEFA1A3 expression in a mouse model of UTI.
  • To establish a foundation for exploring DEFA1A3 manipulation as a therapeutic strategy for UTIs.

Main Methods:

  • Generation of human DEFA1A3 gene transgenic mice (DEFA).
  • Stimulation of human and DEFA mice with uropathogenic Escherichia coli (UPEC) in vitro and in vivo.
  • Analysis of kidney transcriptional and translational expression patterns.
  • Assessment of UTI and pyelonephritis protection in DEFA mice.

Main Results:

  • Kidney expression patterns of human DEFA1A3 were similar in humans and DEFA mice upon UPEC challenge.
  • DEFA mice demonstrated protection against UTI and pyelonephritis under various UPEC challenges.
  • The study validates the transgenic model for investigating DEFA1A3 function.

Conclusions:

  • Human alpha-defensins 1-3 play a significant role in protecting the urinary tract from infection.
  • DEFA1A3 expression confers protection against uropathogenic Escherichia coli.
  • Targeting the DEFA1A3 locus and alpha-defensin expression presents a potential therapeutic avenue for UTIs and other infections.
Keywords:
antimicrobial peptidescollecting ductsmolecular biologypyelonephritistransgenic mouse

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