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Research Project

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Osaka University
Research Institute for Microbial Diseases

Research Theme :
Molecular analysis of host responses against bacterial virulence factors.


Principal Research Scientist
Yasuhiko Horiguchi
Profile:
Research:

1987 - 1990, Research Fellow at The Kitasato Institute.
Project: "Molecular pathogenesis of B. bronchiseptica"
1990 - 1992, Research Fellow at the Research Institute for Microbial
Diseases, Osaka Univ.
1992 - 1998, Research Associate at the Research Institute for Microbial
Diseases, Osaka Univ.
1998 - 2001, Associate Professor at the Research Institute for Microbial Diseases, Osaka Univ.
2001 - Present, Professor at the Research Institute for Microbial Diseases, Osaka Univ.
Project: "Structure and function of bacterial protein toxins"

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Collaborators

Masami Miyake
(Dept. Bacterial Toxinology, Research Institute for Microbial Diaseases, Osaka Univ.)
Kiyomasa Oka
(Dept. Bacterial Toxinology, Research Institute for Microbial Diaseases, Osaka Univ.)

Aya Fukui (Postdoctral Fellow of COE)

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Research Summary

Pathogenic bacteria establish infectious diseases by modifying the function of host cells. In other words, various lesions and symptoms of bacterial infections are a direct result of amplifications or reductions in host cellular functions. In this project, we aim to analyze the alterations in host cellular functions caused by virulence factors that are produced by enteropathogenic Escherichia coli (EPEC) and Bordetella pertussis.
EPEC is known to cause infantile diarrhea in developing countries. The bacterium itself neither produces protein cytotoxins, nor invades intestinal epithelial cells, but is thought to cause diarrhea by altering the barrier function of epithelial cell layers. In fact, EPEC colonization of the epithelial cell layer has been observed to dynamically change the structure of the apical membrane of the epithelial cells. Furthermore, the paracellular pathways of the cell layer become leaky, and the barrier function of the epithelial cells eventually collapses. We have recently found that molecular signals are elaborately transduced between EPEC and epithelial cells during bacterial colonization. We will further dissect the host response to each EPEC virulence factor and examine any EPEC response, which may occur against the host response.
Bordetella pertussis is the cause of whooping cough, a respiratory infection, which causes a characteristic paroxysmal cough in patients. B. pertussis is a purely human pathogen; therefore, animal models of B. pertussis infection that reproduce whooping cough have not yet been established. In contrast, B. bronchiseptica, which shares many virulence factors and protein toxins with B. pertussis, has a wide range of susceptible hosts. Recently, the genomes of both species have been sequenced; this enables us to analyze the genetic differences between B. pertussis and B. bronchiseptica. In this project, we will compare the structures, functions, and cellular responses of B. pertussis and B. bronchiseptica virulence factors. In addition, we will elucidate the mechanism by which B. pertussis colonizes host tissue and analyze bacterial and host determinants which define host susceptibility. We believe that the results of this project should aid in the understanding of host responses against other bacterial infections.

Abnormally bristling microvilli on epithelial cells infected by EPEC.

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Publications

1. Masuda, M., Betancourt, L., Matsuzawa, T., Kashimoto, T., Takao, T., Shimonishi, Y.
and Horiguchi, Y. (2000) Activation of Rho through a cross-link with polyamines catalyzed by Bordetella dermonecrotizing toxin. EMBO J., 19, 521-530.

2. Horiguchi, Y. (2001) Escherichia coli cytotoxic necrotizing factors and Bordetella
dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases. Toxicon, 39, 1619-1627.

3. Masuda, M., Minami, M., Shime, H., Matsuzawa, T. and Horiguchi, Y. (2002) In vivo
modifications of small GTPase Rac and Cdc42 by Bordetella dermonecrotic toxin. Infect. Immun., 70, 998-1001.

4. Shime, H., Ohnishi, T., Nagao, K., Oka, K., Takao, T. and Horiguchi, Y. (2002)
Association of Pasteurella multocida toxin with vimentin. Infect. Immun., 70, 6460-6463.

5. Matsuzawa, T., Fukui, A., Kashimoto, T., Nagao, K., Oka, K., Miyake, M. and
Horiguchi, Y. (2003) Bordetella dermonecrotic toxin undergoes proteolytic processing to be tranlocated from a dynamin-related endosome into the cytoplasm in an acidification-independent manner. J. BIol. Chem., in press.

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