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Bacteria as the basis for new regenerative therapies

Medical microbiologists do not just investigate germs in order to combat them. Now scientists are working on putting infection mechanisms to the use of regenerative medicine.

Bartonella henselae bacteriaare normally very harmless. However, in immunocompromised people these bacteria can lead to a swelling of the lymph nodes or might cause benign blood vessel tumours. That is one of the reasons why they have been subjected to intensive research. Scientists at the Institute of Medical Microbiology and Hygiene at the University of Tübingen discovered Bartonella adhesion A, BadA for short, an extremely long surface protein that plays an important part in the course of infection.

BadA binds to extracellular proteins of the basal membrane of blood vessels, thereby enabling bacterial cells to dock to the endotheliumi, a cell layer that coats the inside of blood vessels. In addition, BadA-forming Bartonella prevent the natural cell death of endothelial cells, which leads to abnormal cell proliferation and eventually to the generation of tumours. However, BadA also has a function that makes the bacteria interesting for application in regeneration biology: the protein promotes angiogenesis (formation of blood vessels). BadA achieves this effect by stimulating the formation and release of host growth factors such as VEGF (vasculoendothelial growth factor).

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BadA as seen under the electron microscope. The ‘hairy’ B. henselae adhesin protein mediates the binding of the bacteria to extracellular matrix proteins and endothelial cells and triggers an HIF-1 medicated host cell response. (Photo: Institute of Medical Microbiology and Hygiene, Tübingen)

"We are the first research group that has been able to use a particular protein to show that bacteria have an effect on angiogenesis," said Prof. Dr. Ingo Autenrieth, Medical Director of the Institute of Medical Microbiology and Hygiene. Autenrieth and his colleague Dr. Volkhard Kempf are working on a concept that will allow them to use the protein for the therapeutic stimulation of angiogenesis. This would be of great advantage in numerous regenerative medical approaches, for example, in autologousi transplants (cultured in the laboratory from the patient’s own cells) that need to be diffused with blood vessels in order to supply the transplant with nutrients.

Programming bacteria so that they promote the formation of blood vessels

"We are working on the development of vehicles with which BadA can be introduced into the organism.Attenuated bacteria, which are also used in vaccinations, can be used as such vehicles," explains Autenrieth. However, BadA is not the only protein that can be used for therapeutic purposes. Adhesin is a member of a protein family that is prevalent in many bacterial species and whose functions have not been clarified in detail. For the time being, Autenrieth and his team are focusing on BadA. They hope to clarify its structure and investigate the whole range of its effects. "When we have a model then we will be able to develop an inhibitor, which in turn will have therapeutic potential," says Autenrieth.

The research into pathogenic intestinal bacteria might also lead to new regenerative concepts. "For example, we would like to use probiotic bacteria that have a protective effect on the intestinal epitheliumi," says Autenrieth who is carrying out intensive research on probiotics in cooperation with his colleague Dr. Julia Frick. However, he is also aware of the problems associated with functional examinations of the intestinal mucosa. "It is very difficult to investigate interactions in the intestines; that’s why we are working with Prof. Dr. Thomas Skutella from the Institute of Anatomy as he has developed an excellent intestinal model. This helps us carry out meaningful tests in vitroi under controlled conditions." Amongst other things, the researchers are examining the protein patterns that useful and harmful bacteria display in an intestinal environment. These patterns might give important hints for therapeutically interesting proteins, which will then be characterised in greater detail.

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B. henselae-infected endothelial cells. Intracellular bacteria are dyed blue, the cytoskeleton (actin) is labelled in red. (Photo: Institute of Medical Microbiology and Hygiene, Tübingen)

Microbial metabolic proteins might prepare the ground for stem cells

Autenrieth also envisages that bacteria might one day be used to support stem cell therapies. "Bacteria can specifically be used to create a stem-cell friendly environment in the target tissue," said Autenrieth. It might be possible for the bacteria to create this environment by releasing their natural metabolic products. It is also possible that genetic engineering might cause the microbes to secrete the required substances.

"In general, research into the metabolic interactions between microorganisms and the human organism are a major topic that will certainly occupy us for the next 10 to 15 years," says Autenrieth, who hopes that it will be possible to deduce as many regenerative approaches as possible. In this sense, bacteria have an absolutely positive model character.

leh - 29.9.2006
© BIOPRO Baden-Württemberg GmbH, first published at www.bio-pro.de<, the Biotech/Life Sciences Portal of the State of Baden-Württemberg. All rights reserved.

More information:

Universitätsklinikum Tübingen
Institut für medizinische Mikrobiologie und Hygiene

Prof. Dr. Ingo B. Autenrieth
(Ärztlicher Direktor)

Elfriede-Aulhorn-Str. 6
72076 Tübingen
Phone: 07071 29-82349
Fax: 07071 29-3435
ingo [dot] autenrieth [at] med [dot] uni-tuebingen [dot] de
www.medizin.uni-tuebingen.de/mikrobiologie/<