Combined Program on Microbiology and Immunology. Osaka University.

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Research Theme :
Analyses of Molecular Mechanisms of Bacterial Toxi-infectious Diseases

Principal Research Scientist
Nakaba Sugimoto
Profile:

1974 Assistant Professor, Internal Medicine, Kanazawa Medical University
1977-1981 PhD course, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
1981 PhD in Immunology from the Australian National University
1981-1986 Member, Basel Institute for Immunology
1987-1992 Head, Department of Immunology, The Tokyo Metropolitan Institute of Medical Science
1993-2001 Professor, Osaka University School of Medicine
2001- Professor, Osaka University Graduate School of MedicineOther Chairman, Ph.D. program committee, Osaka University Graduate School of Medicine

Collaborators

Yuji Isegawa
Associate Professor, Laboratory of Applied Bacteriology, Graduate School of Medicine, Osaka University
Toru Tobe
Associate Professor, Laboratory of Applied Bacteriology, Graduate School of Medicine, Osaka University

Hiroyuki Abe (Research Associate of COE)

Research Summary

Elucidation of the relationships between the mechanisms of action of protein toxins produced by clostridia, anaerobic spore-forming bacteria, and the symptoms of the infectious diseases caused by these bacteria has been Professor Sugimoto’s lifelong research theme. We discovered that the bolus intravenous injection of tetanus toxin to experimental animals elicited flaccid paralysis similar to botulism. Accordingly, we have examined the blockage of neuromuscular transmission by tetanus toxin using mouse phrenic nerve-diaphragm preparations. The results showed that the concentration-response curve of tetanus toxin is very similar to that of botulinum toxin type B, but is clearly different from that of botulinum toxin type A. Taken together, it was determined that the targeting of tetanus toxin is the same as that of botulinum toxin type B, but differs from that of botulinum toxin type A.
We have also found that the cytotoxic effects of C. perfringens enterotoxin can be ascribed to calcium influx, and to its function in forming an ion channel. Furthermore, we identified the toxin-receptor protein by cloning the receptor gene, and demonstrated that the toxin receptor is expressed in intestinal epithelial cells and hepatic cells.
In addition, we have reported that a thiol-activated hemolysin does not possess a direct cardiotoxic effect. The hemolysin significantly enhances the vascular resistance in parenchymal organs in addition to the heart. This result prompted us to analyze the toxicogenic effects of hemolysin in the vascular system. We discovered that the hemolysin specifically inhibited the endothelial cell-derived relaxing effect on the vascular smooth muscle, and that the cardiotoxic effect of the SH-activated hemolysin can be attributed to coronary vasoconstruction caused by the abnormal endothelial cell function.
Clostridium septicum is a bacterium which elicits the highly lethal gas gangrene. It is noteworthy that we demonstrated that intravenous injection of the alpha toxin produced by this bacterium causes cardiogenic shock. Moreover, we reported that the toxin directly affects cardiac muscle, which results in significant damage to contraction. When the concentration of alpha toxin was decreased, the spontaneous contraction of atrial muscles was disrupted whereas electrical stimulus was still able to elicit cardiac muscle contraction. Therefore, we showed that this toxin targets the specific conduction system of the heart.
Currently, our focus is to investigate in detail the relationships between the aforementioned toxins and the symptoms of the diseases. In addition, we have started research projects to determine the mechanism by which vomiting is induced by staphylococcal enterotoxin, and the clinical cause of unique cardiac failure due to diphtheria toxin.

Clostridia, bacteria belonging to a genus Clostridium, produce various protein toxins. The neurotoxins produced by C. tetani and C. botulinum specifically degrade proteins, called SNAREs, required for fusion of synaptic vesicle membranes and presynaptic membranes at the nerve terminal. Degradation of SNAREs inhibits neurotransmission and causes motor neuropathy. C. perfringens enterotoxin elicits calcium influx into intestinal epithelial cells, which results in damage of the epithelial cell layer and causes a food poisoning. In addition, the enterotoxin disrupts hepatic cells in a similar manner and causes death in animals. SH-activated hemolysin affects the intravascular endothelium, inhibiting the release of endothelium-derived relaxing factor (EDRF). This results in disruption of the bloodstream due to vascular contraction and in dysfunction of various organs. C.septicum alpha toxin directly affects the heart, causing damage to the specific conduction system, and finally spontaneous heart contraction.

Publications

1. Abrami, L., M. Fivaz, P. E. Glauser, N. Sugimoto, C. Zurzolo, and F. G. van der Goot.
2003. Sensitivity of polarized epithelial cells to the pore forming toxin aerolysin. Infection and Immunity. 71: 739-746.

2. Hong, Y., K. Ohishi, N. Inoue, J-Y, Kang, H. Shime, Y. Horiguchi, F. G. van der Goot,
N. Sugimoto, and T. Kinoshita. 2002. Requirement of N-glycan on GPI-anchored proteins for efficient binding of aerolysin but not Clostridium septicum á-toxin. The EMBO Journal. 21: 5047-5056.

3. Sugimoto, N., and M. Matsuda. 2002. Motor neurons. In Site-specific neurotoxicity. D.
S. Lester, J. N. Johannessen, W. R. Slikker and P.Lazarovici, editors. Taylor & Francis Inc. pp 167-179.

4. Saito, T., I, Miyai, T. Matsumura, S. Nozaki, J. Kang, H. Fujita, N. Sugimoto, and N.
Yuki. 2000. A case of Bickerstaff's brainstem encepharitis mimicking tetanus. Journal of Neurology, Neurosurgery and Psychiatory, 69, No5: 695-696.