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Dynamic Bladder and Bacterial Changes Hold Clues to Therapies

In two recent studies, researchers delved into changes that occur in the bladder and invading bacteria that affect both acute and recurrent infection. Repeated infections in women with a history of UTI are not always due to the same strain of UPEC or even to E. coli, and the majority of UPEC studies have been performed in “infection-naïve” mice—those that had no prior infection. Thus, there is a need to better understand how and what changes occur in the bladder during acute infection affect susceptibility to future infection, and how microbes have adapted to use these changes to persist in the bladder.

In one study, investigators examined more closely the impact of a history of UTI on risk for recurrent UTI. Similar to what is seen in human UTIs, mice infected with UPEC, in the absence of antibiotic treatment, have different outcomes—some spontaneously resolve the infection within a couple of weeks, while others go on to develop a chronic infection. To study the interaction of these outcomes with future infection, the researchers developed an experimental mouse model. They infected female mice with a standard UPEC strain commonly used in the laboratory, and separated mice in which the infection spontaneously resolved from mice that became chronically infected after 4 weeks. They then provided both groups with a 4-week convalescent period of antibiotic treatment. (A third, control group of mice was mock-infected but otherwise treated the same way.) Subsequently, the researchers exposed the three groups of mice to a fresh dose of UPEC. They found that the group of mice that previously developed chronic infections was predisposed to develop severe, recurrent infection, whereas mice from the spontaneously resolving group developed mild, acute infections that were quickly over, earning these groups the titles of “sensitized” and “resolved,” respectively. The researchers then compared how sensitized, resolved, and naïve mice reacted to infection with several different strains of E. coli associated with urinary tract infections in people as well as a non-E. coli bacteria that can also cause UTIs. They found that the sensitized mice were highly susceptible to developing chronic infections from these strains, whereas virtually all of the resolved mice did not develop any chronic infection at all from these strains. These observations in mice suggest that a history of UTI and whether it resolved or became chronic could have an important impact on susceptibility to future infection.

Microscopic examination of the experimental model mouse bladders revealed dramatic structural changes. Cells at the surface of the bladder lining were smaller in both sensitized and resolved compared to naïve mice, whereas sensitized mice showed additional changes in deeper tissue layers that were suggestive of incomplete repair and regeneration of the bladder lining during convalescence. Intriguingly, results of other experiments suggested that this bladder remodeling also altered the dynamics of UPEC infection. Two further experiments shed light on possible targets for therapy. One experiment indicated that heightened susceptibility to chronic infection in sensitized mice is likely driven by a pro-inflammatory factor called cyclooxygenase-2 (COX-2). Treating sensitized mice with a COX-2 inhibitor prior to second infection with UPEC ameliorated the burden of infection. The other experiment demonstrated that vaccination against a UPEC protein essential to infection also protected sensitized mice from developing either acute or chronic infections. Important to potential translatability to humans, defects in the bladder lining have been observed in human chronic and recurrent UTI. Thus, such therapeutic targets could be useful if UTI-induced bladder changes and their impact as revealed in this study in mice turn out to occur similarly in some people.

In a second study, scientists focused on a specific UPEC factor and learned critical new information about its role in persistent UTIs. UPEC carry on their surface a number of protein fibers, called pili (singular: pilus), that enable them to attach to different surfaces. It has long been known that specific pili, called type 1 pili, are essential to UPEC’s ability to initiate infection. The pili are tipped with adhesive domains that enable binding to specific receptor molecules in the bladder lining and facilitate bacterial invasion of bladder cells. The adhesive domains are referred to as “adhesins.”

Through experiments in female mice, the researchers discovered that whereas the type 1 pilus adhesin, called FimH, enables UPEC to adhere to the cells at the surface of a healthy (“naïve”) bladder lining at the outset of infection, UPEC then deploy a second type of pilus with a different adhesin, called FmlH, that adheres specifically to infected, inflamed bladder lining.

This appears to occur as the superficial cells bound by FimH are shed during the bladder response to acute infection, exposing inflamed tissue bearing the target for FmlH binding. Notably, additional experiments indicated that the expression of the target is likely increasing as inflammation-induced remodeling of the bladder tissue occurs. The deployment of the second type of pilus provides an advantage in establishing chronic infection in a mouse model: UPEC lacking FmlH were much less effective at causing or maintaining chronic infection in mice. When the researchers tested a vaccine against FmlH in mice, they found that vaccinated mice initially had the same bacterial burden as mock-vaccinated mice, but within 2 to 3 days of infection the burden dropped significantly; the vaccine thus protected the mice against progression of infection. This study reveals a mechanism by which UPEC have adapted to and leveraged the host response to acute infection to their advantage, and a new therapeutic target that could help halt chronic or recurrent infection in its tracks.

References

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