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Abstract: SA-PO605

The Human Ribonuclease 3 Antimicrobial Peptide Reduces Urinary Tract Infection Susceptibility In Vivo

Session Information

  • Pediatric Nephrology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1800 Pediatric Nephrology

Authors

  • Cortado, Hanna H., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kercsmar, Macie M., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Li, Birong, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Gupta, Sudipti, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ching, Christina B., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Spencer, John David, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ruiz-Rosado, Juan de Dios, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Group or Team Name

  • Kidney and Urinary Tract Center
Background

Urinary tract infections (UTI) are common, serious bacterial infections of childhood, most often caused by uropathogenic Escherichia coli (UPEC). To develop innovative and effective strategies to prevent and treat UTI, we have focused our efforts toward identifying antimicrobial peptides (AMPs) that exhibit potent activity toward UPEC in vitro and in vivo. Here, we utilized a genetic approach to study the contributions of human Ribonuclease (RNase) 3 to UTI susceptibility in mice.

Methods

Urine RNase3 levels were measured by ELISA in females with UTI and compared to unaffected controls. Humanized RNASE3 transgenic mice underwent transurethral inoculation of UPEC, and CFU were enumerated in urinary tract organs. We utilized immunofluorescence microscopy and intracellular flow cytometry to identify the cellular sources of RNase3. The bactericidal activity of RNase3 toward UPEC was investigated through the use of recombinant RNase3 and RNASE3 transgenic neutrophils.

Results

Urine RNase3/Cr levels were elevated in patients with UTI compared to controls. RNase 3 amino-terminal peptide exhibited dose-dependent killing of UPEC. RNASE3 transgenic mice were protected from ascending UPEC infection, with reduced upper tract bacterial burden, compared to non-transgenic controls. RNase3 protein is expressed by neutrophils that infiltrate the infected kidney and bladder and release RNase3 following UPEC exposure. Accordingly, compared to non-transgenic controls, RNASE3 transgenic neutrophils are more adept at extracellular UPEC killing.

Conclusion

Our data establish that RNase3 is a neutrophil derived antimicrobial peptide induced during human UTI with potent bactericidal activity toward UPEC. Functionally, our in vitro and in vivo data in RNASE3 transgenic mice and neutrophils establish that RNase3 effectively limits the disseminated UPEC infection.

Funding

  • NIDDK Support