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Why Immune Balance Matters in UTI Susceptibility

Why Immune Balance Matters in UTI Susceptibility 1024 459 Pam Georgiana
Graphic illustration of kidneys and bladder organ visualization. Healthcare concept background with medical icons.

New research identifies PTEN as a main regulator of bladder immunity and suggests potential non-antibiotic prevention strategies.

Urinary tract infections (UTIs) remain among the most common bacterial infections in clinical practice, contributing to significant morbidity and raising concerns about antibiotic resistance. While known risk factors, including lack of circumcision, kidney disease, diabetes and immunosuppression, help explain susceptibility in some patients, they do not fully account for why many individuals develop recurrent infections.

A new study, published in Life Science Alliance, offers insight into this gap. Researchers at Nationwide Children’s Hospital found that effective urothelial defense depends not simply on activating immune pathways, but on maintaining those responses within a tightly controlled range.

John D. Spencer, MD, nephrologist, principal investigator and co-director of the Kidney and Urinary Tract Center in the Abigail Wexner Research Institute at Nationwide Children’s, has spent more than a decade studying UTI susceptibility.

“We’ve identified a number of clinical risk factors over the years, but a large portion of patients still develop infections,” says Dr. Spencer, who is also professor of Pediatrics at The Ohio State University College of Medicine. “That suggests there are underlying biological mechanisms that we don’t fully understand.”

The research team focused on phosphatase and tensin homolog (PTEN), an enzyme that suppresses the PI3K/Akt signaling pathway. This is the central pathway that regulates how cells grow, survive and respond to stress or infection. Prior research suggested that activating this pathway could enhance the body’s defense against infection. The team hypothesized that removing PTEN and increasing pathway activity might improve bacterial clearance. Instead, they observed the opposite effect.

Using both human urothelial cell models and urothelial-specific PTEN knockout mice, the researchers found that PTEN loss increased susceptibility to uropathogenic Escherichia coli (E. coli) infection. Bacterial attachment, invasion and intracellular survival were all elevated in PTEN-deficient cells. In the mice, this resulted in higher bacterial burdens in the urine, bladder and kidneys.

“We thought that if we took the brakes off completely, we might see greater protection against bacteria, especially E. coli,” Dr. Spencer says. “We did not see that. The bladder cells were actually more susceptible to infection.”

Further analysis showed that PTEN deficiency disrupted downstream signaling, particularly involving NF-κB and focal adhesion kinase (FAK). Although NF-κB is typically associated with pro-inflammatory responses, sustained activation appeared to blunt effective immune signaling.

“At a high level, you would expect more inflammation,” Dr. Spencer says. “But what we saw suggests that prolonged activation may actually lead to a kind of immune exhaustion or burnout, increasing infection risk.”

At the same time, FAK overexpression altered urothelial cell structure, facilitating bacterial entry.

“FAK is involved in how cells adhere to each other,” Dr. Spencer explains. “When it’s overexpressed, it makes it easier for E. coli to get inside the cells.”

Importantly, inhibiting either NF-κB or FAK restored resistance to infection in PTEN-deficient cells, confirming these pathways as key drivers of susceptibility. Together, these findings highlight the importance of balanced immune signaling in the bladder, where both insufficient and excessive pathway activation can impair host defense.

Clinically, the study points to potential non-antibiotic strategies for prevention. “We don’t have many options to prevent infections outside of antibiotics,” Dr. Spencer says. “Targeting pathways like FAK or NF-κB could be a future approach, especially for patients with recurrent UTIs.”

The findings also suggest that screening for PTEN dysfunction or downstream pathway activation may help identify patients at higher risk for recurrent infection. However, further validation in human populations is needed.

Dr. Spencer’s research demonstrates a broader principle in host-pathogen interactions: effective immunity depends on balance. “The cells in our body can protect against infection, but it’s a finely tuned system,” Dr. Spencer says. “We need to better understand where that optimal range is.”

 

 

Reference:

Simoni A, Bochter MS, Linn-Peirano S, Salamon K, Becknell B, Cortado H, Jackson AR, Schwartz L, Spencer JD. PTEN modulates urinary tract infection susceptibility and shapes urothelial antibacterial defenses. Life Science Alliance. 2025 Jul 23;8(10):e202503292. doi: 10.26508/lsa.202503292.

Image credit: Adobe Stock

About the author

Pam Georgiana is a brand marketing professional and writer located in Bexley, Ohio. She believes that words bind us together as humans and that the best stories remind us of our humanity. She specialized in telling engaging stories for healthcare, B2B services, and nonprofits using classic storytelling techniques. Pam has earned an MBA in Marketing from Capital University in Columbus, Ohio.

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