Ribonuclease 7 Shields the Kidney and Bladder from Invasive Uropathogenic Escherichia coli Infection
Year: 2019
Type: article
Abstract: Significance Statement In 80% of urinary tract infections (UTIs), uropathogenic Escherichia coli is the causative pathogen. Evidence suggests that antimicrobial peptides protect the kidneys and bladder from bacterial challenge. The authors previously identified ribonuclease 7 (RNase 7) as an antibacterial peptide produced by human kidneys and bladder. In this study, they found significantly lower urinary RNase 7 concentrations in girls and female adolescents with a UTI history compared with controls. They also demonstrated that silencing RNase 7 expression in human urothelial cultures increased uropathogen susceptibility, whereas its overexpression conferred protection. In vivo , humanized RNase 7–expressing transgenic mice showed protection against uropathogenic E. coli challenge compared with controls. These findings suggest that RNase 7 has potential as a UTI prognostic marker or a therapeutic target for protection against bacterial infection. 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.
Institutions: The Ohio State University, Nationwide Children's Hospital
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Roles and Regulation of Ribonuclease 6 in Defending the Urinary Tract Against Bacterial Infection, Novel Mouse Models to Assess the in vivo Significance of Ribonuclease 7 in Urinary Tract Defense, Linking Insulin Signaling to Antimicrobial Peptide Production and the Kidney's Antibacterial Defenses, The Contribution of Ribonuclease 7 to Urinary Tract Anitbacterial Defense, Role of urothelium in epithelial integrity and innate defense of the kidney, Cancer Center Support Grant
OpenAlex ID: W2954143340