Chemistry: molecular biology and microbiology – Vector – per se
Patent
1991-03-14
1994-02-22
Wax, Robert A.
Chemistry: molecular biology and microbiology
Vector, per se
530300, 530327, 530328, 530329, 530330, 530350, 530371, 530806, 530823, 435921, 435922, 435924, 536 2374, 935 9, 935 11, 935 12, C12N 1531, C12N 1563, C07K 500, C07K 700, C07K 1300
Patent
active
052886395
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to fungal stress proteins, to corresponding DNA sequences, to fungal stress protein inhibitors and to their use in medicine and for diagnosis.
BACKGROUND TO THE INVENTION
Environmental stress can induce an increase in the rate of synthesis of so-called heat shock, or stress, proteins in both procaryotic and eucaryotic cells [see for example Schlesinger et al (eds) in Heat Shock from Bacteria to Man, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1972)]. Although the function of stress proteins has yet to be finally resolved, some have been reported to participate in assembly and structural stabilisation of cerain cellular and viral proteins, and their presence at high concentration may have an additional stabilising effect during exposure to adverse conditions.
Many pathogenic organisms have been shown to produce stress proteins [see for example Young D, et al, Proc. Natl. Acad. Sci. USA 85, 4267-4270 (1988)]. The proteins are thought to be produced in response to the stress of infection to help protect the invading pathogen. Thus, for example, the ability to produce stress proteins has been implicated in the survival of bacterial pathogens within macrophages [Christmas, M. F. et al, Cell, 41, 753-762 (1985) and Morgan, R. W. et al, Proc. Natl. Acad. Sci. USA, 83, 8059-8063, (1986)].
It has been suggested that the presence of stress proteins in a variety of human pathogens indicates that the stress response is a general component of infections, and that stress proteins should be considered among candidates for subunit vaccines [Young, D. et al, ibid].
Candida albicans is, medically, the most important of the human fungal pathogens. Systemic candidiasis (candidosis) is an increasingly common cause of death amongst immunocompromised and debilitated patients, with a mortality of over 70% [Gold, J. W. M., Am. J. Med. 76, 458-463, (1984)]; while oral candidiasis is a frequent early manifestation of the acquired immunodeficiency syndrome [Klein, R. S. et al, N. Engl. J. Med. 311, 354-357, (1984)]. Candidiasis is difficult to diagnose, and is not easy to treat, mainly since the usual method of treatment involves use of amphotericin B, which is itself highly toxic. A need therefore exists in the diagnosis and treatment of Candida infections for more sensitive diagnostic methods and treatment which has less toxic side effects.
A number of Candida antigens have been detected in the sera of patients with systemic candidiasis [Matthews, R. C. et al, J. Clin. Microbiol. 25, 230-237 (1987)]. One of these, with a relative molecular mass of approximately 47 kilodaltons (47 kd) is an immunodominant antigen which has been reported by four independent groups [Matthews R. C., et al Lancet ii, 1415-1418 (1984); Au-Young, JK et al, Diagn. Microbiol. Infect. Dis., 3, 419-432, (1985); Neale T. J., et al, Aust. N. Z. J. Med., 17, 201-209 (1987); and Ferreira R. P. et al, J. Clin. Microbiol. 28, 1075-1078 (1990)]. This 47 Kd antigen is distinct from the 48-52 Kd antigen described by Strockbine et al [Strockbine N. A. et al Infect. Immun. 43, 715-721 (1984)] for two reasons:
(1) monoclonal antibodies raised against the 48-52 Kd antigen cross-react with antigens at 120-135 Kd and 35-38 Kd [Strockbine N. A. et al, Infect Immun 43, 1012-18 (1984); Buckley H. R., et al U.S. Pat. No. 4670382 (1987)] and
(2) the 48-52 Kd antigen it is an enolase [Safranek W. W. and Buckley H. R., Second Conference on Candida and Candidiasis, Abstract A7 (1990]. In contrast, antibody to the 47 Kd antigen cross-reacts with an antigen at about 92 Kd (see below). An immundominant C. albicans antigen of 54.3 Kd (range 48.9 to 59.7 Kd) was described by Greenfield R. A., and Jones J. M., in Infect. Immun. 34, 469-477 (1981).
SUMMARY OF THE INVENTION
We have now been able to clone and express part of the DNA sequence encoding the 47 Kd antigen, and in doing so we have surprisingly discovered a polypeptide sequence which has significant sequence homology with known stress proteins from other organisms,
REFERENCES:
patent: 4732852 (1988-03-01), Cohen et al.
Matthews et al., "Immunoblot Analysis of the Serological Response in Systemic Candidosis", Lancet, pp. 1415-1418, Dec. 22-29, 1984.
Matthews et al., "Isolation of Immunodominant Antigens from Sera of Patients with Systemic Candidiasis and Characterization of Serological Response to Candida Albicans" Journal of Clinical Microbiol., 25(2):230-237, 1987.
Matthews et al., "Characterization and Cellular Localization of Immunodominant 47 KDa Antigen of Candida Albicans", Journal of Medical Microbiology, 27:227-232, 1988.
Neale et al., "The Immunochemical Characterization of Circulating Immune Complex Constituents in Candida Albicans Osteomyelitis by Isoelectric Focusing, Immunoblot and Immunoprint", Aust. NZ. J. Med., 17:201-208, 1987.
Matthews, et al. 1989 FEMS Microbiology Letters 60:25-30.
Burnie, J. P. et al. 1985 Lancet No. 8438 p. 1155.
Young, R. A. et al. 1983 Proc. Nat. Acad. Sci., U.S.A. 80:1194-1198.
Farrelly, T. W. et al. 1984 Jour. Biol. Chem. 259:5745-5751.
Burnie James P.
Matthews Ruth C.
Bugaisky Gabriele E.
The Victoria University of Manchester
Wax Robert A.
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