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Loss of RNase 6 Increases Susceptibility to Upper Urinary Tract Infections, Model Shows

Loss of RNase 6 Increases Susceptibility to Upper Urinary Tract Infections, Model Shows 1024 575 Katie Brind'Amour, PhD, MS, CHES

The latest in a robust series of studies confirms an important role for RNase 6 in deterring infections of the ureters and kidneys.

 

Research teams at the Abigail Wexner Research Institute at Nationwide Children’s Hospital have long been studying a superfamily of ribonucleases for their role as natural antimicrobials in the human urinary tract. In a series of recent publications, these clinician-scientists have established the importance of RNase 6 as a protector of the kidneys and ureters in the fight against uropathogenic Escherichia coli (UPEC), the most common cause of urinary tract infections (UTI).

Two of the studies, both published in the Journal of Innate Immunity, examine the origin and function of RNase 6 in mouse models. The first used transgenic mice with human RNase 6 to verify the ability of RNase 6 to fight off experimental UTI. The study confirmed that mice with the human RNase 6 transgene had lower UPEC burden, reduced signs of mucosal injury, and less inflammation compared to controls. In this study, they also confirmed that RNase 6 is produced by white blood cells (macrophages and monocytes).

Cells expressing RNase6 (bright white, indicated with arrows) are shown migrating toward a collection of bacteria (green, UPEC). The dotted line indicates the bladder lining.

In a follow-up study, the team created a mouse model deficient in RNase 6. This study confirmed that loss of RNase 6 resulted in increased UPEC burden in the upper urinary tract during experimental UTI, and increased survival of UPEC in white blood cells deficient in RNase 6.

“The major thing we’re contributing with this most recent study is that when RNase 6 is deleted, the animals were more susceptible to upper urinary tract infection—the bacteria were more persistent in the ureters and kidneys of RNase 6 knockout mice,” explains M. Brian Becknell, MD, PhD, pediatric nephrologist and principal investigator for the Kidney and Urinary Tract Center at Nationwide Children’s. “Taken together with our other research, we have shown that RNase 6 plays an important role in macrophages intracellularly, after the cells engulph UPEC, to kill bacteria and thereby limit upper tract infection.”

The recent work complements the body of research on RNase 4 and RNase 7 produced by the labs of John David Spencer, MD, chief of the Division of Nephrology and Hypertension and principal investigator in the Center for Clinical and Translational Research, and Laura Schwartz, PhD, principal investigator in the Kidney and Urinary Tract Center, supporting roles for all three RNases in protection of the urinary tract against UPEC. While preliminary screenings of drug libraries have revealed possible candidates for repurposed drugs that may enhance innate production of RNases 4 and 7, the researchers still have a lot to learn before they’re ready to move into the clinic.

“We think there are epithelial- and leukocyte-derived RNases playing important roles in both the lower and upper tract, working in a complementary fashion to cooperatively limit bacteria,” says Dr. Becknell, whose team spearheaded the work on RNase 6. This RNase, though not yet as well understood as the others, could be important in upper-tract diseases such as pyelonephritis and vesicoureteral reflux (VUR)—two conditions that can lead to renal scarring and permanently reduced kidney function. The team plans to examine RNase 6 in a mouse model of VUR and has submitted a grant to that end.

Dr. Becknell hopes that better understanding the role of RNase 6 can have meaningful clinical impact even before its therapeutic potential is explored; another recent article of the team, published this year in the International Journal of Molecular Sciences, revealed that naturally occurring variations in the RNase 6 gene impact its bactericidal activity. One common polymorphism had significantly decreased antimicrobial properties compared to the other common variation.

“We don’t know yet if that results in increased UTI susceptibility in patients, but it certainly begs the question given how common the polymorphism is and the profound difference we saw between these two variants that differ in just a single amino acid,” says Dr. Becknell. “It would be wonderful to be able to identify patients proactively who may be more susceptible to UTIs based on genetic testing.”

 

 

References:

  1. Anguita R, Prats-Ejarque G, Moussaoui M, Becknell B, Boix E. A Common Polymorphism in RNASE6Impacts Its Antimicrobial Activity toward Uropathogenic Escherichia coli. Int J Mol Sci. 2024 Jan 3;25(1):604.
  2. Cortado H, Kercsmar M, Li B, Vasquez-Martinez G, Gupta S, Ching C, Ballash G, Cotzomi-Ortega I, Sanchez-Zamora YI, Boix E, Zepeda-Orozco D, Jackson AR, Spencer JD, Ruiz-Rosado JD, Becknell B. Murine Ribonuclease 6 Limits Bacterial Dissemination during Experimental Urinary Tract Infection. J Innate Immun. 2024;16(1):283-294.
  3. Ruiz-Rosado JD, Cortado H, Kercsmar M, Li B, Ballash G, Cotzomi-Ortega I, Sanchez-Zamora YI, Gupta S, Ching C, Boix E, Jackson AR, Spencer JD, Becknell B. Human Ribonuclease 6 Has a Protective Role during Experimental Urinary Tract Infection. J Innate Immun. 2023;15(1):865-875.

Image credits: Mandy Root-Thompson for Nationwide Children’s (header); Macie Kercsmar, BS, for Nationwide Children’s (microscopy)

About the author

Katherine (Katie) Brind’Amour is a freelance medical and health science writer based in Pennsylvania. She has written about nearly every therapeutic area for patients, doctors and the general public. Dr. Brind’Amour specializes in health literacy and patient education. She completed her BS and MS degrees in Biology at Arizona State University and her PhD in Health Services Management and Policy at The Ohio State University. She is a Certified Health Education Specialist and is interested in health promotion via health programs and the communication of medical information.

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