In the July 15 issue of the journal Genes & Development, a team of Japanese scientists have uncovered how the pathogenic E. coli bacteria cause cell death in their human hosts. These findings may open the door to the development of drugs to combat the devastation of infection by inhibiting cell death caused by the bacteria.
The E. coli bacteria include pathogenic strains that are major causes of diarrhea in developing countries, killing nearly one million children as a result of dehydration and complications from organ failure. The E. coli O157:H7 is a strain that contaminates hamburger and other foods. Ingestion of the contaminated food causes diarrhea and multiple organ failure, as a result of massive cell death in the kidneys and intestines. Nearly 76 million Americans a year get food poisoning and O157:H7 infection alone accounts for approximately 200 fatalities yearly, primarily from kidney failure.
When food is contaminated with the pathogenic E. coli, the bacteria secrete molecules called verotoxins, which are transported in the blood stream of the patient. The verotoxins are taken up by intestinal, blood, and kidney cells, which then are destroyed by the toxins. Although this general cascade had already been known, just exactly how these toxins killed the cells remained a mystery. Now, Drs. Atsushi Suzuki and Hirofumi Doi and their colleagues in Japan discovered that the verotoxins contain a short stretch of amino acids very similar to a sequence within the protein Bcl-2. Bcl-2 is a major player in a cellular process known as 'programmed cell death', in which surplus or damaged cells commit suicide to protect the whole organism from itself. This short amino acid sequence is necessary for Bcl-2 to interact with other proteins. The researchers demonstrated that one particular verotoxin binds to Bcl-2 via this short motif and triggers the cell death program in an otherwise healthy cell. The massive self destruction of the reprogrammed cells leads to tissue destruction and, ultimately, to organ failure.
The finding that this verotoxinBcl-2 complex, through the short peptide motif, was responsible for the cell death hinted at the importance of this feature. Further evidence in support of this mechanism was found when cells treated with the chemically synthesized peptide before invasion by the verotoxin did not undergo cell death. Thus, treating the cells with this short peptide prevents the verotoxinBcl-2 complex from forming and saves the life of the cell.
The reference for this paper is:
Atsushi Suzuki, Hirofumi Doi, Fumiko Matsuzawa, Sei-ichi Aikawa, Kyoko Takiguchi, Hirokazu Kawano, Midori Hayashida, and Susumu Ohno. Bcl-2 antiapoptotic protein mediates verotoxin II-induced cell death: possible association between Bcl-2 and tissue failure by E. coli O157:H7. Genes and Development, Vol. 14, Issue 14, pp. 1734-1740.
Drs. Atsushi Suzuki, Hirokazu Kawano, and Midori Hayashida are at the Project for the Cell Death Research, Basic Technology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Tokyo 134-8630, Japan. Drs. Hirofumi Doi, Fumiko Matsuzawa, Sei-ichi Aikawa, and Kyoko Takiguchi, are at the Biological Informatics Section, Fujitsu Laboratories, Ltd., Chiba 261-0023, Japan. Dr. Doi is also at Doi Bioasymmetry Project, ERATO, Japan Science and Technology Co., Chiba 263-7112, Japan. Dr. Susumu Ohno is at the Beckkman Research Institute of the City of Hope, California 91010-0269, USA. Drs. Suzuki and Doi both contributed equally to this project. Dr. Suzuki is the corresponding author and can be reached by email at firstname.lastname@example.org
Message posted by: Trevor M. D'Souza
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