Why initial UTIs increase susceptibility to further infection

More than 60% of women will experience a urinary tract infection (UTI) at some point in their lives, and about a quarter will get a second such infection within six months, for reasons that have been unclear to health experts.

Now, researchers at Washington University School of Medicine in St. Louis have discovered that an initial infection can set the tone for subsequent infections. In mouse studies, the researchers found that a transient infection triggers a short-lived inflammatory response that rapidly eliminates the bacteria. But if the initial infection lingers for weeks, the inflammation also persists, leading to long-lasting changes to the bladder that prime the immune system to overreact the next time bacteria find their way into the urinary tract, worsening the infection.

To understand why some people are more prone to severe, recurrent infections than others, Hannan and co-senior author Scott J. Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology -- along with co-first authors Lu Yu, PhD, and Valerie O'Brien, PhD, both graduate students when the work was conducted -- infected a strain of genetically identical mice with E. coli, the most common cause of UTIs in people. The strain can have widely divergent responses to bacterial bladder infections. Some eliminate the bacteria within a few days; others develop chronic infections that last for weeks.

The researchers infected these mice with E. coli, monitored them for signs of infection in their urine for four weeks, and then gave them antibiotics. After giving the mice a month to heal, the researchers infected them again. For comparison, they also infected a separate group of mice for the first time.

All the previously infected mice mounted immune responses more rapidly than the mice infected for the first time. The ones that had cleared the infection on their own the first time around did so again, eliminating the bacteria even faster than before. But the mice that failed to clear the infection the first time did much worse, despite the speed of their immune responses. A day after infection, 11 out of 14 had more bacteria in their bladders than they had started with, and many went on to again develop chronic infections that lasted at least four weeks.

The difference lay in an immune molecule called TNF-alpha that coordinates a powerful inflammatory response to infection, the researchers discovered. Both sets of mice turned on TNF-alpha within six hours of infection. But the mice that controlled the infection turned off TNF-alpha again within 24 hours, allowing the inflammation to resolve. In the mice with prolonged initial infections, TNF-alpha stayed on, driving persistent inflammation and triggering a change to the patterns of gene activity in immune cells and the cells of the bladder wall.

To find out, the researchers took mice that had recovered from initial prolonged UTIs and depleted their TNF-alpha before re-infecting them with bacteria. Without TNF-alpha driving excessive inflammation, the mice fared better, significantly reducing the number of bacteria in their bladders within a day of infection.

The findings suggest that targeting TNF-alpha or another aspect of the inflammatory response that causes bladder tissue damage during acute infection may help prevent or alleviate recurrent UTIs, the researchers said.

See:

Lu Yu, Valerie P O'Brien, Jonathan Livny, Denise Dorsey, Nirmalya Bandyopadhyay, Marco Colonna, Michael G Caparon, Elisha DO Roberson, Scott J Hultgren, Thomas J Hannan. Mucosal infection rewires TNFɑ signaling dynamics to skew susceptibility to recurrence. eLife, 2019; 8 DOI: 10.7554/eLife.46677

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology