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uni'wissen 1-2013_ENG

Hygiene is a top priority at hospitals – but that doesn’t stop the bacterium Clostridium difficile from proliferating and causing life-threatening intestinal infections with a toxin. Klaus Aktories and his team want to develop a drug that alleviates the course of the disease. Photo: Britt Shilling/Freiburg University Medical Center skillful manipulation, the scientists established haploid cell lines, each of which was missing a different gene, and then infected these cultures with CDT. The only cells that survived were the ones in which the toxin could not take effect because its receptor was missing. The subse­ quent genome analysis confirmed that LSR was indeed the culprit. This discovery earned the researchers the Phoenix Pharmaceutical Science Award, worth 10,000 euros. Introducing Toxins into Cancer Cells Aktories plans to use the same method to find the receptor of the toxin TpeL in C. perfringens. The bacterium causes gas gangrene, a wound infection that quickly leads to death if left untreated. TpeL does not act primarily on the cytoskeleton. It deactivates the protein Ras, an important switch for cell proliferation, cell differ­ entiation, and cancer. “Ras is mutated in almost 40 percent of all tumors,” says Aktories, “in pan­ creatic cancer even in nine out of ten cases.” All previous attempts to develop a therapy have failed because scientists did not know of any substance that blocks Ras – until now. TpeL has the potential to cure cancer or at least alleviate Invasion under the microscope: The rod-shaped bacterium Clostridium difficile (right) attacks the actin fibers in the cytoskeleton, which helps the cell to keep its shape, by means of a toxin. The previ- ously intact skeleton (upper left) becomes thinner and porous (lower left). Photos: Klaus Aktories would be an agent that only takes effect in the intestine, where C. difficile is present one out of 25 people, in hospitals even in one out of every five patients. Those who actually get sick from the infection are usually older than 65, take anti­ biotics, and often suffer from other severe illnesses. Antibiotics damage bacteria of the normal intestinal flora, allowing the C. difficile bacteria to develop freely. Their toxins cause diarrhea and inflammation of the intestines. The frequency, severity, and danger of the infections have increased in recent times due to a proliferation of hypervirulent or highly infective strains. Their deadliest weapons are the toxins A and B. “Without them, no one gets sick,” explains the scientist. To make matters worse, hypervirulent strains are resistant to certain antibiotics, and they produce CDT. This toxin attacks the cytoskeleton, which stabilizes the cell and keeps its shape intact. “There is a high probability that the toxin aggravates the course of the infection,” says Aktories. His colleague Dr. Carsten Schwan shows a microscopic video of the cytoskeleton, in which the microfilaments, forming a framework of fibers made of the pro­ tein actin, resemble a spider’s web. It becomes thinner and porous when CDT attacks. In addi­ tion, tentacle­like structures begin growing out of the cells, forming a network on the cell surface the C. difficile bacteria can use to latch on to the cell. “The bacterium creates its own little niche and makes itself right at home,” explains Schwan. In order to penetrate into the cells, CDT binds to the protein LSR on the intestinal cells. In cooperation with the cancer researcher Dr. Thijn Brummelkamp from Amsterdam, Netherlands, Aktories and his team identified the receptor by means of “gene trapping.” This method works with haploid cells, which contain only a single set of genes instead of the normal double set. With their help, errors in the genes can be iden­ tified immediately, because there are no “copies” that could compensate for defects. Through 37