Medical Professional Publications

Triggering Host Antimicrobial Peptide Production During UTI

(From the April 2018 issue of Research Now)

The signaling pathway that triggers a natural defense against the common infection could help yield an alternative to antibiotics.

Researchers trying to understand how the body responds to bacteria in the urinary tract have found key elements that appear to trigger the machinery mounting a defense.

Recent experiments at The Research Institute at Nationwide Children’s Hospital, show a pair of signaling proteins, interleukin-6 (IL-6) and STAT3, are important in defense mechanisms in response to urinary tract infection (UTI). These mechanisms rely in part on naturally produced antimicrobial peptides.

The research team published their study in Kidney International, and hopes this work could be an advancement towards finding alternative treatments for UTIs, rather than continuing to rely on antibiotics. 

“UTIs are a significant problem in children, and they can lead to long-term consequences, such as renal scarring, in addition to causing the immediate stress on the family and discomfort for the patient,” says Christina Ching, MD, a urological surgeon and principal investigator in the Center for Clinical and Translational Research at The Research Institute at Nationwide Children’s Hospital. Dr. Ching is the lead author of the study. 

“Tools to determine who is susceptible and how they should be treated are limited,” says Dr. Ching, who is also an assistant professor of pediatric urology at The Ohio State University College of Medicine. “We typically use antibiotics; however, these have side effects and foster the development of drug-resistant bacteria.  We are in search of alternative treatment options to tackle UTIs and ways to predict an increased susceptibility to UTI to better target at-risk patient populations.”

Brian Becknell, MD, PhD, a nephrologist and principal investigator in the same center, is the senior study author and one of several current and former Nationwide Children’s researchers who have identified a variety of antimicrobial peptides expressed in the urinary tract in response to infection and have been studying their role in UTI prevention and clearance. 

“We continue to build on prior work on antimicrobial peptides to try and better understand how they are regulated and their involvement in UTI susceptibility.  ” says Dr. Becknell, who is also an assistant professor of pediatrics at The Ohio State University College of Medicine.

The recent study used a mouse model of UTI to show that the tissue lining the urinary tract secretes IL-6 in response to Escherichia coli, the most common bacteria causing UTI.  They went on to show that the presence of IL-6 activates the transcription factor STAT3, resulting in synthesis of antimicrobial peptides.

Loss of IL-6 or STAT3 expression resulted in lower antimicrobial peptide production, and an increase in UTI susceptibility. Conversely, administration of IL-6 to IL-6 deficient mice reduced UTI severity. 

In a model of chronic UTI, the authors also showed that depletion of IL-6 increased renal bacterial burden and severity of kidney injury.

Drs. Ching and Becknell are continuing to further investigate exactly how IL-6/STAT3 signaling and antimicrobial peptide expression alter UTI susceptibility. 

In addition, they plan to pursue translational studies in order to determine the relevance of their findings in children.  For example, Dr. Ching is in the process of determining if IL-6 signaling is altered in children with bladder versus kidney infections, and if these alterations predict the risk of developing renal scarring.  

“If we understand more about the signaling pathways involved in developing an UTI, we can target that response to help with treatment,” Dr. Ching says.

Citation: Ching CB, Gupta S, Li B, Cortado H, Mayne N, Jackson AR, McHugh KM, Becknell B. Interleukin-6/Stat3 signaling has an essential role in host antimicrobial response to urinary tract infection. Kidney International. 2018 Feb 20. pii: S0085-2538(18)30031-0. [Epub ahead of print]

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