Bladder ‘memory’ influences recurrence of urinary tract infections in mice
OOne of the main challenges in the treatment of urinary tract infections is their high recurrence, especially in women. The mechanisms underlying this high recurrence rate are not well understood, but having suffered from a previous UTI is an important factor risk factor. A study in mice published on April 10 in Natural microbiology proposes that this may be partly explained because an initial urinary tract infection with Escherichia coli– the culprit of most cases of UTI – alters the host epithelial epigenome in such a way that it alters bladder morphology in the long term, influencing the response to future infections with the same bacterium.
“When people think about how our body fights pathogens, they focus on the immune system,” says Shruti Naik, an immunologist at NYU Langone Health who was not involved in this study. She adds that this work shows “clear evidence that changes occur in epithelial cells. . . have long-term consequences for how we respond to infections.
Some of the researchers behind the new study had already reported in 2016 than mice infected with a first E.coli UTIs resulted in either spontaneous resolution or chronic cystitis, reducing or increasing susceptibility to future infections, respectively. The researchers then found that, in each scenario, the E.coli UTI had differentially altered the bladder epithelium in terms of architecture, morphology, and molecular signatures. This motivated them to study the phenomenon in detail, wondering, for example, if this remodeling occurs in “the environment of the bladder as a whole.” . . Or [if it is] something intrinsic to the epithelium,” says Thomas Hannana mucosal immunologist from Washington University in St. Louis who worked on both studies.
See “Abundant bacteriophages in female bladder”
To do this, they first isolated epithelial stem cells from mice with resolved or chronic infection, and cultured them to see if the cells continued to show noticeable differences, as they had done in vivo. Indeed, the fully differentiated bladder epithelium formed by these cells in vitro mimicked the morphological alterations previously observed in each group of mice. The difference between the two resulting fabrics was “striking,” says Hannan. This suggested that there was “something hereditary” in the cells leading to these phenotypes, he adds, “and so we hypothesized that it was an epigenetic change.”
They were right. When Hannan and his colleagues performed a series of genomic analyzes on the cells, they found “a different imprint on the epigenome depending on the initial history of the disease, and . . . some of these could explain the phenotypes we’ve seen,” he says. These epigenetic alterations, namely chromatin accessibility, DNA methylation, and histone modifications, affect the expression of multiple genes.
For example, the team found that the expression of caspase-1, a gene involved in immune cell responses against microbial infections, was significantly upregulated in the differentiated epithelium of cells from mice with chronic cystitis, while it was almost absent in those from mice. with resolved infections as well as cells from control mice that were not exposed to E.coli. Caspase-1 induces cell death, which helps get rid of infected cells, but it also promotes inflammation and mucosal damage, leading to increased susceptibility to recurrent infections. So the epigenetic changes seen in mice with chronic cystitis aren’t necessarily “all bad,” says Hannan, “there’s a reason why we might develop ‘responses like this’ – “they’re good in the moment, but they may not always be good”. in all circumstances. »
The fact that the same changes in the bladder epithelium can be induced in vivo and in vitro suggests that the underlying epigenetic changes “are stable and directly linked to genes associated with an innate immune defense mechanism against the bacterium” . Gerard Hoynean immunologist from the University of Notre Dame Australia who was not involved in this work, writes in an email to The scientist.
Translating these findings into humans – for example, to treat recurrent UTIs – is still a distant goal, all sources agree. “A lot of other technologies would need to be in place,” says Hannan, adding that we need a “better understanding of how you can manipulate the epigenome in a very directed way” in order to develop such therapies. Hannan is Scientific Director of Therapeutic Fimbriona company specializing in the development of antimicrobial drugs to treat infectious diseases.
But the take-home message is that “when we think about infectious disease responses, we really need to start integrating this idea that the immune system [works] together with the rest of the fabric,” says Naik, who previously reported a similar case inflammatory memory in mouse skin.