How the body fights urinary tract infections


How the body fights urinary tract infections

A larger scale shows how uromodulin filaments (blue) envelop an E. coli cell, thus preventing the pathogen pili from trapping on cell walls in the urinary tract and causing an infection. The image is a 3D visualization from electron tomography measurements. Credit: Gregor Weiss / ETH Zurich

Some people are better protected than others against urinary tract infections. This may be because their bodies make more than one protein called uromodulin. An interdisciplinary research team has discovered exactly how this helper protein provides relief when nature calls it, and how this knowledge could benefit the treatment and prevention of these painful inflammations.

Anyone who has had cystitis knows that urinary tract infections of this type are bothersome and painful. They can be treated well with antibiotics, but they can be fatal if left untreated. These infections are generally caused by what are known as uropathogenic E. coli bacteria when they bind to the cells of the bladder, ureter, or urethra with their pili, the thread-like appendages that grow out of them like hairs. But protection is available in the form of a certain protein, naturally produced in the body, called uromodulin. About 70 percent of all people carry a variant of the uromodulin gene in their genome, which means that they produce this protective protein in particularly large quantities. Consequently, they have a lower risk of contracting urinary tract infections.

But the exact process by which uromodulin prevents inflammation has never been understood. Now, an interdisciplinary team, made up of three research groups at ETH Zurich together with researchers from the University of Zurich and Children’s Hospital Zurich, has filled this knowledge gap by investigating the appearance of uromodulin and how the protein neutralizes E. uropathogenic coli. Their findings, which have been published in the journal. ScienceIt should help develop new strategies for treating urinary tract infections in the future.

A detailed look at how it works

First, the researchers looked at how the protein binds to the bacterial pili at the molecular level. “We already knew that a bond is formed and that this presumably plays a role in the protective role of uromodulin, but no one had studied this in more detail,” says Gregor Weiss, a PhD student in molecular biology at ETH and one of the authors. of the study. . Their biochemical investigations have now shown that bacterial pili recognize certain sugar chains on the surface of uromodulin and bind to them extremely easily and strongly.

The team then examined uromodulin using cryoelectron tomography, an imaging technique that produces three-dimensional views of the structure of proteins and cells without the need for chemical modification or dehydration. This showed them that uromodulin forms long filaments consisting of an average of about 400 individual protein molecules bound together. And that each link in this protein chain contains the characteristic pattern of the sugar chains to which the bacterial pili bind.

Fruitful collaboration

Cryoelectron tomography was also the technique chosen by the team to investigate on a larger scale what effect these properties have, this time in the presence of the culprits, the uropathogenic bacterium E. coli. They found that uromodulin filaments literally envelop the pathogen, and that a single uromodulin filament can mate with multiple pili from a bacterium. “This neutralizes pathogens,” explains Weiss: “Once bacteria are protected in this way, they can no longer bind to cells in the urinary tract, which means they cannot cause infection.” Under a light microscope, the team also observed the formation of large groups of hundreds of uromodulin filaments and E. coli cells, which are presumably simply excreted in the urine.

Finally, the researchers verified if all these processes that they had observed in the laboratory also occur in patients. They analyzed urine samples from infected patients provided by the Zurich Children’s Hospital and found exactly the same interactions between uromodulin and pathogens. “Without interdisciplinary collaboration between different research groups and institutes, it would have been impossible to obtain this set of findings,” says ETH professor Martin Pilhofer, who led the electron tomography research.

Pointers for drug treatment and development.

The research team’s work offers advice on how to treat and prevent urinary tract infections without using antibiotics. Until now, patients have often been given preparations containing mannose sugar. To some extent, they prevent E. coli bacteria from attaching to cells in the urinary tract. “Thanks to our analyzes, we now know that bacterial pili recognize not only mannose but also other sugars present in uromodulin,” says Jessica Stanisich, a doctoral student and another lead author of the study. “This could indicate that treatment with combined sugar supplements would be more effective.”

The new findings also help in the development of new active substances, adds ETH professor Rudi Glockshuber. This is because during an infection, uropathogenic E. coli attaches to the same sugar chains on the cell surfaces of the urinary tract as it does to uromodulin. Pharmaceutical companies seek to identify new active substances that precisely prevent these interactions, but this also runs the risk of disrupting the protective binding of uromodulin to the bacteria. “Obviously it would be a highly undesirable side effect for a drug if that treatment simultaneously interferes with a natural protective function,” says Glockshuber. However, the research team’s analyzes have now shown that the bonds between bacteria and uromodulin are extremely stable and cannot be broken down by active substances, an important finding in the search for remedies for unpleasant urinary tract infections.


3D images reveal the body’s guardian against UTI.


More information:
GL Weiss al al., “Architecture and function of human uromodulin filaments in urinary tract infections” Science (2020). science.sciencemag.org/cgi/doi… 1126 / science.aaz9866

Citation: How the Body Fights Urinary Tract Infections (2020, July 2) Retrieved on July 2, 2020 from https://medicalxpress.com/news/2020-07-body-urinary-tract-infections.html

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