Ribonuclease 7 Shields the Kidney and Bladder from Invasive Uropathogenic Escherichia coli Infection.

Abstract

BACKGROUND:

Evidence suggests that antimicrobial peptides, components of the innate immune response, protect the kidneys and bladder from bacterial challenge. We previously identified ribonuclease 7 (RNase 7) as a human antimicrobial peptide that has bactericidal activity against uropathogenic Escherichia coli (UPEC). Functional studies assessing RNase 7's contributions to urinary tract defense are limited.

METHODS:

To investigate RNase 7's role in preventing urinary tract infection (UTI), we quantified urinary RNase 7 concentrations in 29 girls and adolescents with a UTI history and 29 healthy female human controls. To assess RNase 7's antimicrobial activity in vitro in human urothelial cells, we used siRNA to silence urothelial RNase 7 production and retroviral constructs to stably overexpress RNase 7; we then evaluated UPEC's ability to bind and invade these cells. For RNase 7 in vivo studies, we developed humanized RNase 7 transgenic mice, subjected them to experimental UTI, and enumerated UPEC burden in the urine, bladder, and kidneys.

RESULTS:

Compared with controls, study participants with a UTI history had 1.5-fold lower urinary RNase 7 concentrations. When RNase 7 was silenced in vitro, the percentage of UPEC binding or invading human urothelial cells increased; when cells overexpressed RNase 7, UPEC attachment and invasion decreased. In the transgenic mice, we detected RNase 7 expression in the kidney's intercalated cells and bladder urothelium. RNase 7 humanized mice exhibited marked protection from UPEC.

CONCLUSIONS:

These findings provide evidence that RNase 7 has a role in kidney and bladder host defense against UPEC and establish a foundation for investigating RNase 7 as a UTI prognostic marker or nonantibiotic-based therapy.

• Authors: Tad Eichler, Kristin Bender, Matthew J Murtha, Laura Schwartz, Jackie Metheny, Lindsey Solden, Robert M Jaggers, Michael T Bailey, Sudipti Gupta, Claudia Mosquera, Christina Ching, Krista La Perle, Birong Li, Brian Becknell, John David Spencer
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 30 Issue 8 Pg. 1385-1397 (08 2019) ISSN: 1533-3450 [Electronic] United States
• PMID: 31239387 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 by the American Society of Nephrology.

Chemical References

• Anti-Bacterial Agents
• Antimicrobial Cationic Peptides
• Ribonucleases
• Ribonuclease 7

Topics

• Adolescent
• Animals
• Anti-Bacterial Agents (pharmacology)
• Antimicrobial Cationic Peptides (genetics)
• Child
• Child, Preschool
• Escherichia coli Infections (enzymology)
• Female
• Gene Silencing
• Humans
• Immunity, Innate
• Infant
• Kidney (enzymology, microbiology)
• Male
• Mice
• Mice, Transgenic
• Phenotype
• Prognosis
• Ribonucleases (genetics)
• Urinary Bladder (enzymology, microbiology)
• Urinary Tract Infections (enzymology, microbiology)
• Uropathogenic Escherichia coli
• Urothelium (metabolism, pathology)
• Young Adult