As Toxins Activate Cellular Directory

A diarrheal pathogens changes the surface of intestinal cells so that bacteria can better settle

Clostridium difficile
Bacterial toxins form cell processes and use this as a guide Septins. Picture: Carsten Swan

The use of antibiotics often damages the natural intestinal flora. This can consequently no longer hold pathogenic germs at bay; Diarrhea and intestinal inflammation may occur. Among the pathogens is one of the germ Clostridium difficile , the intestinal cells attack by toxins. The bacterium causes, among other things, that a fine network of cell processes formed on the surface of intestinal cells, thereby further bacteria can better colonize.

The working group of Prof. Dr. Klaus Aktories and Dr. Carsten Swan from Department of Pharmacology University of Freiburg has shown how the toxin CDT from C. difficile bacteria these cell processes forms. The scientists have published their findings in the journal “Proceedings of the National Academy of Sciences of the United States of America ” (PNAS). “As we examine the CDT toxin, we can better understand how intestinal inflammation caused by the pathogens and develop,” says Aktories. “In addition, we can clear up basic physiological processes by taking advantage of the toxin as a tool.” Particularly aggressive bacteria of the species C. difficile produce toxins that destroy the cytoskeleton of intestinal cells. This contact between intestinal cells and their place functions are inhibited, resulting in typical diarrhea and inflammation. Two major components of the cytoskeleton are actin and microtubules, which play a central role in the maintenance of cell shape, the barrier function and in cellular processes of motion. The CDT toxin of C. difficile altered actin and thereby blocks the chain formation, interfering with its normal function. One consequence is that form microtubules chains easier and multiply such that numerous cell processes occur. These form a network on the intestinal cell surface and promote contact of the bacteria with the host cell. As CDT makes these cell processes, was previously unknown.

The Freiburg scientists have shown that the influence of the toxic substance on the interaction of the two scaffold proteins actin and tubulin dependent on a third device, the septins. In a human cell, there are up to 13 different Septins that interact with each other and can be connected to chains, rings or bands. This process is called polymerization. CDT changes the actin so that the septins can no longer bind to actin, and instead migrate to the cell membrane. Here they form funnel-like Septinpolymere that the microtubules – tubular protein structures – to grow. Septins stand with the tip of growing microtubules directly interact and function so as a signpost for the growth of these structures. The investigation of Freiburg workgroup also allow insights into the development of Septin funnel. The proteins Cdc42 and Borg regulate the transport of Septins to the membranes and are a prerequisite for the formation of the hoppers. A similar function as in the foothills formation that causes the toxin CDT, have Septins in the human nervous system in the formation of nerve foothills, the neurites. Again, there is an interaction of actin, microtubules and septins where microscopically similar structures are formed.

The investigation of the toxin therefore provides insights into underlying processes in the human body. Klaus Aktories is Director, Division I at the Institute of Experimental and Clinical Pharmacology and Toxicology at the Albert Ludwigs University and a member at the Freiburg BIOSS Centre for Biological Signalling Studies. Carsten Swan is a research associate in the laboratory of Aktories.