Building on their body of research focused on the naturally occurring antimicrobial peptides in the urinary tract, clinician-scientists at Nationwide Children’s Hospital have now confirmed the suspected role of Ribonuclease 7 (RNase 7) in E. coli-based infection risk. Human patients, tissue cultures and humanized mouse models all indicate that higher levels of RNase 7 in the urinary tract are associated with lower risk of infection, and lower levels of RNase 7 are associated with increased susceptibility to infection. According to the research team, this suggests a potential role for RNase 7 in the prediction of infection risk or severity as well as in the development of novel, non-antibiotic treatments — even for drug-resistant UTIs.
“For the first time, we’ve shown that female children with UTIs have lower levels of the antimicrobial peptide RNase 7 compared to healthy controls,” says John David Spencer, MD, chief of the Division of Nephrology at Nationwide Children’s and senior author on the study, published in August in the Journal of the American Society of Nephrology. The study’s 29 girls who had a UTI history had an average urinary RNase 7 concentration 1.5 times lower than the 29 healthy control girls.
In addition, the publication included findings from human tissue cultures showing that silencing RNase 7 allowed a multi-drug resistant strain of E. coli (known as uropathogenic E. coli or UPEC) to bind more effectively to human bladder cells, while overexpressing RNase 7 led to decreased bacterial binding.
The team also developed a humanized mouse model to express high and low levels of RNase 7 in the urinary tract in order to study its biological activity. This first-ever manipulation of RNase 7 in vivo revealed that mice with RNase 7 present had low susceptibility to infection when challenged with UPEC.
“In this paper we showed that RNase 7 is able to kill multi-drug resistant E. coli,” says Dr. Spencer. “The list of antibiotic-resistant pathogens is growing by number every day, so perhaps this is way we can treat antibiotic-sensitive infections and antibiotic-resistant infections as well.”
These natural peptides may be operationalized to treat infections in one of two ways, Dr. Spencer expects. The first possibility is to synthesize peptides in a lab and administer them by mouth or directly into the bladder or bloodstream. The other is to find a method to manipulate other pathways in the body to indirectly drive up natural RNase 7 expression to fight infection.
“This study represents a key step in trying to evaluate the biological activity and safety profile of RNase 7 manipulation,” says Dr. Spencer, whose work on antimicrobial peptides is supported by funding through the National Institutes of Health. “Our research suggests that if you can find way to overexpress the RNase 7 protein, it could be a therapy. It also further validates that if you have lower levels of RNase 7, you may be at greater risk for infection.”
The clinical research team is tracking RNase 7 levels over time in patients with recurrent UTIs and investigating methods for turning RNase 7 manipulation into a realistic treatment option. The team may have already uncovered one pathway-based alternative to boost RNase 7 levels: giving insulin. Additional recent research from Dr. Spencer and his colleagues has shown it drives up the body’s production of antimicrobial peptides, including RNase 7.
“The ultimate dream would be to use RNase 7 as both a biomarker and a natural way to boost the body’s ability to fight or prevent infection,” says Dr. Spencer. “It would be ideal to know who is at greatest risk, be able to counsel them on how to avoid infection, and also be able to treat them more or less homeopathically should the need arise.”
Eichler T, Bender K, Murtha MJ, Schwartz L, Metheny J, Solden L, Jaggers RM, Bailey MT, Gupta S, Mosquera C, Ching C, La Perle K, Li B, Becknell B, Spencer JD. Ribonuclease 7 Shields the Kidney and Bladder from Invasive Uropathogenic Escherichia coli Infection. J Am Soc Nephrol. 2019 Aug;30(8):1385-1397.
Murtha MJ, Eichler T, Bender K, Metheny J, Li B, Schwaderer AL, Mosquera C, James C, Schwartz L, Becknell B, Spencer JD. Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses. The Journal of Clinical Investigation. 2018 Dec 3;128(12):5634-5646.