Urinary tract infections (UTIs) reoccur easily, in part, because one type of bladder immune cells is slow to develop immune memory, finds a Science Immunology study in mice. While the results are too preliminary to inform clinical guidelines for treating UTIs, the new work spotlights a less-studied cell population that could be exploited by researchers during the UTI vaccine creation process.
"By understanding how we develop memory to this infection, we can use this knowledge to develop therapies such as vaccination or immunomodulation," said Matthieu Rousseau, the first author on the paper who investigates the nuances of bladder immunity with corresponding author Molly Ingersoll at the Institut Pasteur and Institut Cochin.
While examining the behavior of bladder immune cells in mice with UTIs, Rousseau, Ingersoll and their colleagues also observed that the timeframe for delivering antibiotics to mice with UTIs seemed to have some influence on how well some cells called resident memory T cells created memory of the infecting bacteria.
"This is an idea that absolutely requires more testing in preclinical studies and humans," said Ingersoll. "It's important to add that we are not advocating that individuals with a UTI delay starting a course of antibiotics."
Bacteria That Bounce Back
Even when treated with antibiotics, UTIs have a reputation for recurrence. The bacteria that cause them — including the most widespread type, E. coli — are very good at bouncing back.
"Both preclinical and clinical studies have shown that the bacteria that cause the infection can form reservoirs in the bladder and the gut. By living inside cells, bacteria could potentially escape elimination by antibiotics and later emerge to cause a new infection," said Ingersoll and Rousseau.
In the past, if a doctor saw a patient who had frequent UTIs, they might prescribe a low dose of antibiotics for roughly six months or longer. While this clinical approach is still helpful in certain cases, it can sometimes encourage UTI-causing microbes to evolve drug resistance.
"Urinary tract infection is the second most common reason for prescribing antibiotics and a prime example of the antibiotic crisis," said Rousseau, citing the World Health Organization as a reference to learn more about antibiotic resistance. "When antibiotics do work, they only treat the current infection but cannot prevent a future recurrent infection. New non-antibiotic-based therapies are urgently needed, or UTI will become impossible to treat."
Beyond tenacious drug-resistant bacteria, immune cell activity might also contribute to the likelihood of UTI recurrence in some people. The team previously published a 2020 Science Advances mouse study that revealed the existence of two subsets of bladder residing macrophages and described how those macrophages influence the region's response to infection and re-infection. Over the past few years, other analyses have indicated that immune cells within the urinary tract writ large may have poor memory.
Since immune memory is a central tenet of vaccination, the urinary tract's memory deficit makes it harder to derive a UTI vaccine that could circumvent the need for chronic antibiotic use.
By examining bladder immune cells in female mouse models of primary and recurrent UTIs, the scientists found that one way in which the bladder's mucosal layer reacts to UTI-causing E. coli is by encouraging the growth of bacteria-specific tissue resident (TRM) cells. This was a surprising observation that challenged what was thought about how the immune system might facilitate UTI cycles. Existing theories suggested that T cells in the bladder transformed into a T helper cell subset that prioritized repairing tissue over eradicating bacteria, essentially enabling E. coli to regrow and resume infection. However, Rosseau and Ingersoll did not see a tissue repair-centric pathway happen in their mice in the lab.
"We tested this hypothesis, finding that bladder T cells differentiate into all types of helper subsets during infection, without a specific bias towards just one type," said Rousseau. "It was this result that led us to find the special type of memory T cells that live in the tissue after an infection in the bladder and mediate protection to recurrent UTI."
Upon further investigations, the authors saw that if antibiotics were given to mice early in infection, too much E. coli died and an insufficient amount of TRM cells formed, leading to weak memory when re-infected. The optimal time to give drugs to the mice seemed to be around 48 hours after the start of infection.
"When we waited 48 hours, the negative impact on immune memory and T cell numbers was gone," said Ingersoll. She stressed that while this phenomenon might suggest that a slight delay in treatment could help improve bladder immune memory, it is far too soon to extrapolate how the findings might impact the treatment for UTIs in people.
"This idea needs to be tested in humans before making blanket statements about the risk of antibiotic treatment, especially in light of its benefits in clearing infection," said Rousseau and Ingersoll.
Several hurdles must be cleared before any changes are made to existing clinical UTI protocols. First, immunologists must determine whether humans even have bladder TRM cells that perform similarly to those in mice. This process requires invasive bladder biopsies. Second, there needs to be a way to pin down exactly when UTIs begin. Doing so is far more difficult in humans than in laboratory mice. Without knowing the precise start of infection, not much can be done to optimize the delivery of antibiotics.
"Developing new therapies for infection, that rely less on antibiotics or can even eliminate the need for antibiotics, should be a priority," said Ingersoll and Rousseau.
Their laboratory group is motivated to conduct future experiments surrounding the nuances of bladder immune memory. For example, they plan to look for biomarkers that might indicate the existence of TRM cells in humans, which would bypass the need for bladder biopsies. Those human TRM cells could be targeted by UTI vaccines to strengthen immune memory against pathogenic urinary tract bacteria.
"Our results suggest that a vaccine strategy that promotes the development of tissue resident memory T cells would be beneficial to prevent recurrent UTI. This idea needs to be tested in animals first," Ingersoll said.