The secret path of prostate infections

Confocal microscopy images showing that E. coli (red) preferentially adheres to luminal prostate cells (green) in human prostate tissue.
Image Credit: Maria Guedes & Carmen Aguilar

Scientific Frontline: "At a Glance" Summary

• Main Discovery: Researchers elucidated the precise entry mechanism of Escherichia coli into prostate tissue, proving the invasion is a highly coordinated process targeting specific cell types rather than a random occurrence.
• Methodology: The team developed a novel "mini-prostate" organoid model using adult stem cells, which accurately replicates the architecture and cell diversity of human prostate epithelium to observe infection dynamics in real-time.
• Specific Detail/Mechanism: The infection utilizes a "lock-and-key" mechanism where the bacterial protein FimH binds specifically to the Prostatic Acid Phosphatase (PPAP) receptor found on the surface of luminal prostate cells.
• Key Statistic or Data: Laboratory experiments demonstrated that the sugar molecule D-mannose significantly reduced infection rates by acting as a "decoy," binding to bacterial FimH proteins and preventing them from attaching to host cells.
• Significance/Future Application: These findings identify D-mannose as a potential non-antibiotic therapeutic for bacterial prostatitis, addressing the critical need for alternatives to antibiotics in the face of rising resistance.
• Context: Bacterial prostatitis affects approximately 1% of the male population worldwide, with relapse rates exceeding 50% within a year despite long-term treatment with high-dose antibiotics.

A research team from the University of Würzburg has for the first time elucidated how E. coli bacteria enter the prostate. The discovery reveals new possibilities for the treatment of bacterial prostatitis. 

Bacterial prostatitis, an infection of the prostate that is primarily caused by Escherichia coli (E. coli) caused is a common health problem in men. Globally, about one percent of all men are affected during their lifetime. The infection occurs when bacteria pass from the urethra or bladder into the prostate. Treatment of bacterial prostatitis remains difficult because patients often require long, high-dose antibiotic treatments. Despite treatment, more than half of patients relapse within a year.  

Researchers have long suspected that bacteria invade prostate cells to survive and escape the immune system and antibiotics. However, direct evidence of this survival strategy has been lacking so far. 

Prostate organoid cells whose PPAP receptor has been knocked out (seen here in the two images on the right) show a significantly lower infection rate compared to wild-type cells (left).
Image Credit: Simon Peters & Carmen Aguila

A lab-grown mini-prostate 

Until now, research into prostate infections has been difficult because there were no suitable laboratory models that accurately mimic real tissue. Without the ability to observe infections in the real tissue environment, the development of alternative therapies, beyond antibiotics, was almost impossible. That has now changed. 

A research team from the Julius-Maximilians-University of Würzburg (JMU) has developed a “mini-prostate” organoid model from adult stem cells. This laboratory-grown model mimics the true prostate epithelium in structure and cell diversity. Using this model, scientists were able to understand the infection step by step under realistic, controlled conditions and identify exactly how the bacteria attack. This provides clear indications for the development of targeted countermeasures. 

Dr. Carmen Aguilar, junior research group leader at the Institute of Molecular Infection Biology (IMIB) at the University of Würzburg, led the study together with colleagues from the University Hospital Würzburg (UKW), the Helmholtz Institute for RNA-Based Infection Research (HIRI), and the University of Münster. The team's findings were published in the current issue of the journal Nature Microbiology published. 

The schematic shows that E. coli attaches to luminal prostate cells via its adhesin FimH, thus initiating invasion. This interaction is blocked by D-mannose.
Image Credit: Maria Guedes

The pathway of attack of E. coli decoded 

“We have shown that the invasion of E. coli into prostate cells is not a random process, but a highly coordinated operation that exploits a specific vulnerability in the cellular architecture of the prostate epithelium”, explains Carmen Aguilar. According to her findings, E. coli cannot attack indiscriminately but rather focuses on a specific cell type: the so-called luminal cells, which line the glandular channels of the prostate and are the first to come into contact with the bacteria when these reach the prostate. 

This invasion works according to a “key-lock principle”. The bacterial protein FimH acts as a “key” that fits snugly into a “lock” on the surface of the prostate's luminal cells. The researchers identified this lock as the prostate-specific receptor PPAP (prostate-specific acid phosphatase). “Only when the bacterial protein binds to this prostate receptor, can the bacteria penetrate the cells, multiply safely there and trigger the infection”, explains Aguilar. 

A sugar molecule blocks the infection 

However, the team was not content to discover the route of infection. It also identified a way to block this interaction with a simple sugar molecule called D-mannose. This sugar, already used to prevent and treat cystitis, acts as a “dummy lock”. 

The bacterial “keys” bind this harmless sugar molecule instead of the real receptors on the prostate cells, effectively blocking bacterial penetration into the cells. In the laboratory, the use of D-mannose has already led to a significant reduction in infections, suggesting a possible new strategy for the prevention and treatment of prostate infections. 

Towards alternatives to antibiotics 

The groundbreaking organoid model now provides researchers with a powerful tool to study prostate infections in previously unmatched detail. Using this system, Dr. Aguilar's team is now investigating how E. coli survives and multiplies after penetrating the prostate cells. The model also allows scientists to study the infection strategies of other relevant prostate pathogens such as Klebsiella or Pseudomonas. 

“Given the current antibiotic resistance crisis, our goal is to develop new therapies that can combat E. coli and other bacteria without the use of antibiotics. First, however, we need to fully understand how these infections work”, says Carmen Aguilar. Such approaches could represent an effective alternative to conventional antibiotics and make an important contribution to combating antibiotic resistance. 

Reference Material: What Is: Organoid

Funding: This work was funded by the Federal Ministry of Research, Technology and Space (BMFTR, FiRe-UPec project) and by the German Research Foundation (DFG, GRK 2157 3D Infect). 

Published in journal: Nature Microbiology

Title: Uropathogenic Escherichia coli invade luminal prostate cells via FimH–PPAP receptor binding

Authors: Maria Guedes, Simon Peters, Amruta Joshi, Sina Dorn, Janina Rieger, Kimberly Klapproth, Tristan Beste, Alexander M. Leipold, Mathias Rosenfeldt, Antoine-Emmanuel Saliba, Ulrich Dobrindt, Charis Kalogirou, and Carmen Aguilar

Source/Credit: Julius-Maximilians-University of Würzburg

Reference Number: mcb011226_01

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