1989 Fiscal Year Final Research Report Summary
Dissection of functional structures of pertussis toxin and its application to prophylaxis and medication of whooping cough
| Project/Area Number |
62570199
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
細菌学
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| Research Institution | 国立予防衛生研究所 |
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Principal Investigator |
SATO Hiroko National Institute of Health, Senior Researcher, 体液性免疫部, 主任研究官 (80100080)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Akiharu National Institute of Health, Senior Researcher, 体液性免疫部, 主任研究官 (10100067)
SATO Yuji National Institute of Health, Chief, 細菌部, 室長 (40072889)
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| Project Period (FY) |
1987 – 1989
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| Keywords | Pertussis Toxin / Monoclonal Antibody / Mouse-Protective Antibody / B. pertussis Mutant / Encephalopathy / Pertussis Toxin-neutralizing Antibody / Pertussis Vaccine |
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| Research Abstract |
Pertussis toxin (PT) having very complicated structure and activities is the most important protective antigen in a pertussis vaccine. In order to define the important structural and functional features of PT associated with its pathogenicity and immunoprotectivity, twenty monoclonal antibodies against different parts of PT were characterized. Monoclonal antibodies against subunit 1 (Sl) and subunit 2/3 (S2/3) showed high mouse protectivity in aerosol challenge system but the latter antibodies which recognize common structure between S2 and S3 showed little protection against intracerebral challenge with Bordetelia pertussis. Both protective antibodies showed a significant therapeutic effect on the mice respiratory-infected with the organisms. The other antibodies also showed diverse anti-toxic activities in vitro and in vivo assay systems. The variety of the toxin-neutralizing activities of these antibodies depends on the recognition site of each antibody on PT. Most of anti-S1 antibodies did not show so high neutralization to CHO- cell clustering or histamine-sensitizing activities of PT although anti-S2 and/or S3 did.
Using these monoclonal antibodies, protective antigenicity of various non-toxic PT produced by pertussis mutants or E. coli recombinants were analyzed. Pertussis mutants, 79G, producing stable protective antibens S234 without S1 was developed. The S1 must be unstable because of its replacement of Cys-41 with Tyr. Other genetic toxoids were also developed in E. coli and B. pertussis by change of Arg-9 to Lys and/or Glu-129 to Gly of Sl by site directed mutagenesis. The development of these mutant PT antigens suggests that S1 has the most functional structure for the toxicities of PT.
The study on mouse-encephalopathy caused with PT should be continued further more to develop an animal model for pertussis encephalopathy in human.
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Research Products
(25 results)
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[Publications] Sato, H., Sato, Y., Ito, A., and Ohishi, I.: "Effect of monoclonal antibody to pertussis toxin on toxin activity" Infect. Immun., 55, 909-915, 1987.
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「研究成果報告書概要(欧文)」より
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[Publications] Locht, C., Cieplak, W., Marchitto, K. S., Sato, H., and Keith, J. M.: "Activities of complete and truncated forms of pertussis toxin subunits S1 and S2 synthesized by Escherichia coli" Infect, Immun., 55, 2546-2553, 1987.
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「研究成果報告書概要(欧文)」より
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[Publications] Sato, Y., Sato, H., Ito, A., and Kobayashi, H.: "Isolation of mutant strains producing defective pertussis toxin" Japan. J. Med. Sci. Biol., 40, 192-193, 1987.
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「研究成果報告書概要(欧文)」より
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[Publications] Cieplak, W., Burnette, W. N., Mar, V. L., Kaljot, K. T., Morris, C. F., Chen, K. K., Sato, H. and Keith, J. M.: "Identification of a region in the S1 subunit of pertussis toxin that is required for enzymatic activity and that contributes to the formation of a neutralizing antigenic determinant" Proc. Natl. Acad. Sci., 85, 4667-4671, 1988.
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「研究成果報告書概要(欧文)」より
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[Publications] Burnette, W. N., Cieplak, W., Mar, V. L., Kaljot, K. T., Sato, H. and Keith, J. M.: "Pertussis toxin S1 mutant with reduced enzyme activity and a conserved protective epitope" Science, 242, 72-74, 1988.
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「研究成果報告書概要(欧文)」より
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[Publications] Bartoloni, A., Pizza, M., Bigio, M., Nucci, D., Ashworth, L. A., Irons, L. I., Robinson, A., Burns, D., Manclark, C., Sato, H. and Rappuoli, R.: "Mapping of a protective epitope of pertussis toxin by in vitro refolding of recombinant fragments" Bio/Technology, 6, 709-712, 1988.
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「研究成果報告書概要(欧文)」より
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[Publications] Chazono, M., Nishihara, T., Imaizumi, A., Sato, H. and Sato, Y.: "A mutant strain of B. pertussis (79G6F2) which does not produce subunit S-1 of pertussis toxin" Japan. J. Med. Sci. Biol., 41, 207-208, 1988.
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[Publications] Pizza, M., Covacci, A., Bartoloni, A., Perugini, M., Nencioni, L., De Magistris, M. T., Villa, L., Nucci, D., Manetti, R., Bugnoli, M., Giovannoni, F., Olivieri, R., Barbieri, J. T., Sato, H. and Rappuoli, R.: "Mutant of pertussis toxin suitable for vaccine development" Science, 246, 497-500, 1989.
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[Publications] Sato, H. and Sato, Y.: "Pertussis toxin as a protective antigen." in Bacterial Vaccines, ed. Robbins, J. B., Schneerson, R., Klein, D., Sadoff, J. and Hardegree, M. C. pp. 349-357, Praeger Publishers, 1987, New York.
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[Publications] Burnette, W. N., Mar, V. L., Cieplak, W., Morris, C. F., Kaljot, K. T., Sato, H. and Keith, J. M.: "Toward development of a recombinant pertussis vaccine" in Technological Advances in Vaccine Development, ed. Lasky, L., pp. 75-85, Alan R. Liss, Inc., 1988, New York.
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[Publications] Keith, J. M., Cieplak, W., Kaljot, K. T., Marchitto, K. S., Sato, H., Mar, V. L. and Burnette, W. N.: "Biochemical and immunological analyses of pertussis toxin subunits produced in recombinant Escherichia coli" in Vaccines 88, ed. Ginsburg, H., Brown, F., Lerner, R. A. and Chanock, R. M., pp. 99-103, Cold Spring Harbor Laboratory, 1988, New York.
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