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Poisonous Effect of Intestinal Bacteria Explained

Researchers Use Genetic Procedure to Identify Site of Action of Cytotoxin Produced by “Hypervirulent” Intestinal Flora

Freiburg, Sep 26, 2011

A research group led by Freiburg pharmacologist Prof. Dr. Klaus Aktories and their American colleagues have discovered the cell receptor for the toxin CDT of the bacterium Clostridium difficile. These germs often cause an inflammation of the colon in patients who have recently received a treatment with antibiotics. The results of the study were published in the renowned American journal Proceedings of the National Academy of Sciences (PNAS). Antibiotics damage bacteria of the normal intestinal flora, allowing Clostridium difficile germs to proliferate freely. The germs produce two typical toxins that cause an inflammation in the mucous membrane of the colon and destroy it. The consequences are diarrhea and psudomembranous colitis, an infection that is often lethal in older patients.
Due to the rapid proliferation of Clostridium difficile spores, their resistance to many disinfectants, and the frequent use of antibiotics, infections with Clostridium difficile are a major medical and hygienic problem in hospitals around the world. Particularly alarming is the appearance of so-called hypervirulant strains of Clostridium difficile, which produce more of these typical toxins, are resistant to antibiotics, and also produce a third cytotoxin (CDT) that attacks the cytoskeleton directly.
The Freiburg researchers and their colleagues from the Whitehead Institute, USA, identified the cell receptor of this additional toxin of particularly virulent clostridia. In order to find the receptor, the scientists used a new genetic procedure focusing on cancer cells that only possess one set of chromosomes. These cancer cells are susceptible to the CDT toxin of Clostridium difficile and die off from its poisonous effect. It was already known that this CDT toxin binds to a receptor on the surface of the cells, from where it can penetrate into the cell’s interior by way of a complex procedure. However, the receptor itself was previously unknown.
The researchers succeeded in demonstrating that cells that are resistant to the CDT toxin are made susceptible to it by the receptor. The findings will enable scientists to develop new strategies to prevent the toxin from entering target cells.
The title of the publication: Panagiotis Papatheodorou et. al.: “Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT).”: (Proc Natl Acad Sci U S A. 2011 Sep 19. [Epub ahead of print], doi: 10.1073/pnas.1109772108)
Prof. Dr. Klaus Aktories
Institute of Experimental and Clinical Pharmacology and Toxicology
University of Freiburg
Phone: 0761/203-5301