Some people are better protected against urinary tract infections than others because their bodies may make higher amounts of the uromodulin protein. An interdisciplinary research team has now found out what can be derived from this for the treatment and prevention of painful inflammation.
Results help in the development of new active ingredients
Some people are better protected against urinary tract infections than others because their bodies may make higher amounts of the uromodulin protein. An interdisciplinary research team has now found out how the helper works in relief and what can be derived from this for the treatment and prevention of painful inflammation.
Anyone who has ever had a bladder infection knows: Urinary tract infections like this are bothersome and painful. They can usually be treated well with antibiotics. If left untreated, however, they can also be fatal. Most of the infections are caused by uropathogenic E. coli bacteria. Protection against this is provided by a certain endogenous protein, uromodulin: Around 70 percent of all people carry a uromodulin gene variant in their genome, which means that they produce this protective protein in particularly large quantities. Accordingly, they have a lower risk of contracting urinary tract infections.
But exactly how uromodulin prevents inflammation was not known. An interdisciplinary team from three research groups at ETH Zurich has now discovered this together with researchers from the University of Zurich and the Children’s Hospital Zurich: The researchers examined what uromodulin looks like and by what means it neutralizes uropathogenic E. coli. Their findings have been published in the scientific journal Science and should help to develop new strategies for the treatment of urinary tract infections in the future.
A detailed look at how it works
First, the researchers analyzed at the molecular level how the protein binds to the bacterial pili. “Although it was known beforehand that binding would take place and that this might contribute to the protective function, no further details were known,” says Gregor Weiss, a doctoral student at ETH. The biochemical investigations now showed that the bacterial pili recognize certain sugar chains on the surface of the uromodulin and bind them extremely specifically and strongly.
The team next examined the uromodulin using cryo-electron tomography. The three-dimensional structures of proteins and cells become visible without having to chemically change or drain them. They recognized that the uromodulin forms long filaments. On average, these consist of around 400 individual protein molecules strung together. And every link in this protein chain contains the characteristic pattern of sugar chains to which bacteria pili like to bind.
Fruitful cooperation
The team again looked at the effects of these properties on a larger scale using cryo-electron tomography, but this time in the presence of the culprits, the uropathogenic E. coli bacteria. It was shown that the uromodulin filaments literally envelop the pili of the pathogen. A single uromodulin filament can dock onto several pili of a bacterium. “This neutralizes the pathogens,” explains Gregor Weiss. “Shielded in this way, the bacteria can no longer bind to the cells in the urinary tract and therefore do not trigger an infection.” In the light microscope, the team also recognized that large clumps of hundreds of uromodulin filaments and E. coli cells are formed, which are then probably simply excreted in the urine.
Finally, the researchers checked whether all of these processes observed in the laboratory also take place in patients. To do this, they analyzed urine samples from infected people that the Children’s Hospital in Zurich had provided them with and found exactly the same interactions between the uromodulin and the pathogens. “Without the interdisciplinary collaboration between different research groups and institutes, it would have been impossible to gain this knowledge,” emphasizes ETH Professor Martin Pilhofer, who led the electron tomography studies.
Advice for treatment and drug development
The work of the research team provides indications for antibiotic-free treatment and prevention of urinary tract infections. “From our analyzes, we now know that the bacteria with their pili recognize not only mannose but also other sugars on the uromodulin,” says doctoral student Jessica Stanisich. “This could indicate that treatment with combined sugar supplements would be more effective.”
The new results also help in the development of new active ingredients, adds ETH Professor Rudi Glockshuber. Because uropathogenic E. coli attach to the same sugar chains on the cell surfaces there as in uromodulin when they are infected in the urinary tract. That is why pharmaceutical companies are trying to prevent precisely these interactions with new active ingredients – but with the risk that the binding of the protective uromodulin to the bacteria will also be disturbed. “Of course that would be a highly undesirable side effect if you were to hinder a natural protective function with a medication at the same time,” says Glockshuber. However, the analyzes of the research team now make it clear that the combinations of bacteria and uromodulin are extremely stable and can no longer be broken down by active ingredients – an important finding for the search for agents against the troublesome urinary tract infections.
Those:
Weiss GL, Stanisich JJ, Sauer MM, Lin C, Eras J, Zyla DS, Trück J, Devuyst O, Aebi M, Pilhofer M and Glockshuber R. Architecture and function of human uromodulin filaments in urinary tract infections. Science (2020). Online publiziert 2. Juli 2020. DOI: 10.1126/science.aaz9866
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