Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-10-27
1999-01-12
Sidberry, Hazel F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 237, 536 243, 536 2432, 4352523, 4353201, 435 691, 435 693, 435 911, 4242361, A61K 39106, C12N 1531, C12N 120, C07H 2104
Patent
active
058592199
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a Helicobacter pylori vacuolating toxin, methods to use the toxin in diagnostic testing for the predisposition to peptic ulceration and gastric malignancy, and methods to use the toxin as a vaccine for providing immunologic protection against H. pylori infection.
2. Brief Description of the Background Art
Helicobacter pylori is a curved Gram-negative bacterium that is commonly present in the human stomach; once acquired, this organism persists for years or decades (Blaser, M. J. (1990) J. Infect. Dis. 161:626-633). Multiple lines of evidence now indicate that H. pylori infection nearly universally results in chronic gastritis (Dixon, M. F. (1991) J. Gastroenterol. and Hepatol. 6:125-130). Although most persons with H. pylori-induced gastritis remain asymptomatic, this condition is a significant risk factor for the development of both peptic ulceration and gastric adenocarcinoma (Peterson, W. L. (1991) N. Engl. J. Med. 324:1043-1048, and Nomura, A., Stemmermann, G. N., Chyou, P.-H., Kato, I., Perez-Perez, G. I, and Blaser, M. J., N. Eng. J. Med. 1991; 325:1132-6).
The pathogenesis of H. pylori infection is not yet well understood. The production of high levels of urease by the organism (Dunn, B. E., Campbell, G. P., Perez-Perez, G. I., and Blaser, M. J. (1990) J. Biol. Chem. 265:9464-9469), is thought to be essential for the initiation and maintenance of gastric infection (Eaton, K. A., Morgan, D. R., Krakowka, S. (1989) Infect. Immun. 57:1119-1125). Another potential virulence determinant is a toxin that induces vacuolation of eukaryotic cells (Cover, T. L., Halter, S. A., Blaser, M. J. (1992) Human Pathol. 23:1004-1010. Functionally active toxin is produced in vitro by 50-60% of H. pylori isolates (Leunk, R. D., Johnson, P. T., David, B. C., Kraft, W. G., and Morgan, D. R. (1988) J. Med. Microbiol. 26:93-99 and Cover, T. L., Dooley, C. P., and Blaser, M. J. Infect. Immun.; 58:603-610 (1990)). Antibodies that neutralize toxin activity are present in sera from H. pylori-infected persons, which indicates that the vacuolating toxin activity is relevant in vivo (Leunk, R. D., Ferguson, M. A., Morgan, D. R., Low, D. E., and Simor, A. E. (1990) J. Clin. Microbiol. 28:1181-1184 and Cover, T. L., Cao., P., and Blaser, M. J. (1991) Gastroenterology 100:A570). Two studies have indicated that the prevalence of infection with toxin-producing H. pylori is higher among H. pylori-infected persons with peptic ulceration than among infected persons with gastritis alone (Figura, N., Guglielmetti, P., Rossolini, A., Barberi, A., Cusi, G., Musmanno, R., Russi, M., and Quaranta, S. (1989) J. Clin. Microbiol. 27:225-226; Goosens, H., Vlaes, L., Lambert, J. P., Glupczynski, Y., Burette, A., and Butzler, J. P. (1991) Microb. Ecol. Health Dis. 4:130).
In previous work, the inventors have identified several H. pylori proteins that are present in broth culture supernatants with vacuolating toxic activity, but absent or reduced in concentration in supernatants that lack toxic activity (Cover, T. L., Dooley, C. P., and Blaser, M. J. (1990) Infect. Immun. 58:603-610). In addition, the inventors have demonstrated that the vacuolating toxin is distinct from H. pylori urease (Cover, T. L., Puryar, W., Perez-Perez, G. I., and Blaser, M. J. (1991) Infect. Immun. 59:1264-1270). In this application the inventors describe the purification and characterization of the vacuolating toxin from H. pylori.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a substantially pure antigenic composition with vacuolating toxin activity. This antigenic composition can be either purified from natural material or produced recombinantly.
It is a further object of this invention to provide the gene which can be expressed to provide recombinant vacuolating toxin or fragments thereof. The partial DNA sequence of the gene is set out in sequence Id no. 1.
It is an object of the present invention to provide a purified antigenic composition that specifically
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Blaser Martin J.
Cover Timothy L.
Sidberry Hazel F.
Vanderbilt University
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