Clostridium difficile is a dangerous intestinal bacterium that can cause severe diarrhoea and life-threatening intestinal infections after long-term treatment with antibiotics. Bacteria such as this are becoming increasingly resistant to antibiotics which is why new types of therapy that aren’t based primarily on bacteria are necessary. Now, researchers at the University of Freiburg have identified the molecular docking site that is responsible for the C. difficile toxin’s being able to bind to its receptor on the membrane of the intestinal epithelium.
The team explain that the docking site functions like an elevator, transporting the toxins into the cell’s interior. By binding to the surface receptor, the toxins are able to overcome the cell membrane. Once inside the cell, the C. difficile exerts its full lethal effect. The study is published in the Journal of Biological Chemistry.
Previous studies show that the intestinal pathogen C. difficile is most commonly found in hospitals and is often acquired by older people and people with weakened immune systems. In Western countries, infections with so-called hypervirulent strains of C. difficile are rapidly increasing and are much more dangerous and more difficult to treat. The pathology of C. difficile infections is primarily triggered by two toxins released by the pathogen, which then damage the intestinal epithelium. Particularly dangerous hypervirulent strains produce a third toxin, C. difficile transferase (CDT). This CDT toxin modifies the cytoskeleton, causing the host cells to collapse and die. The team identified the surface protein LSR (lipolysis-stimulated lipoprotein receptor) as the receptor for the CDT toxin already in 2011. It is through the LSR that CDT enters the host cell.
In the current study the researchers identified the regions in the CDT toxin and the LSR receptor that interact with one another. In order to achieve this, the scientists genetically designed truncations of the toxin and the LSR receptor as well as cells without LSR. They then tested whether or not the CDT toxin could bind to its receptor and be absorbed in the cell. They discovered that the parts of the toxin that interact with the receptor are much smaller than previously believed. All that is necessary for toxin absorption is the part of the receptor outside of the cell.
The team hypothesize that in the future, it should be possible to block these areas in the toxin and receptor in order to prevent the toxin from entering the host cell. In the future the lab plan to reduce the toxicological potential of toxins.
Source: BIOSS – Centre for Biological Signalling Studies