Candida albicans is the most common fungal pathogen of humans. Its clinical importance has increased in recent years as the number of immunocompromised patients (AIDS, transplant recipients, cancer, corticosteroid treated, etc.) has expanded and the incidence of opportunistic infections has escalated. The long-term objectives of this grant are to understand the fundamental mechanisms by which pathogenic fungi communicate with each other and with their environment within human hosts, and how host hormones may regulate critical fungal processing during infection. We have described the presence of steroid binding proteins (SBPs) in C. albicans and other pathogenic fungi. These SBPs exhibit high affinity for selected mammalian steroid hormones, particularly estrogens and corticosteroids. We have also demonstrated functional responses in the fungi subsequent to hormone treatment by steroids that bind to the SBPs. These findings have led us to raise 4 hypotheses: (1) the SBPs represent hormone receptors in the fungi; (2) the fungi have endogenous hormones to match each SBP; (3) since the host hormones bind to the SBPs, the fungus responds to the hormonal milieu of the host, thus mediating physiological changes in the invading pathogen; and (4) the SBPs are evolutionarily related to the steroid hormone receptors of higher organisms. We postulate that the host-pathogen interaction contributes to differences in susceptibility to infection depending on the hormonal status of the host (e.g. gender, menstrual stage, pregnancy, treatment with birth control pills or corticosteroids, etc.). The grant will focus on the corticosteroid binding protein (CBP) and the estrogen binding protein (EBP) found in c. albicans.
The aims of the grant will be: (1) to clone the genes encoding the SBPs and raise antibodies to the proteins; (2) using these molecular probes, to define the location and function of the SBPs in C. albicans; (3) among other actions, to evaluate the role of SBPs in regulating cyclic AMP, dimorphism and cellular adhesion, actions that would likely affect fungal pathogenicity; and (4) to explore the evolutionary relationship of the Candida SBPs to homologs in other pathogens, both fungal and protozoan, as well as to other species up the evolutionary tree including human. Our long-range goal is to understand better the biology of pathogenic fungi so that advances can be made in the elucidation of the molecular basis of the epidemiology of human infection and improved methods can be developed for the diagnosis and treatment of fungal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032113-03
Application #
2067014
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1992-01-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Feldman, D; Krishnan, A (1995) Estrogens in unexpected places: possible implications for researchers and consumers. Environ Health Perspect 103 Suppl 7:129-33
Madani, N D; Malloy, P J; Rodriguez-Pombo, P et al. (1994) Candida albicans estrogen-binding protein gene encodes an oxidoreductase that is inhibited by estradiol. Proc Natl Acad Sci U S A 91:922-6
Malloy, P J; Zhao, X; Madani, N D et al. (1993) Cloning and expression of the gene from Candida albicans that encodes a high-affinity corticosteroid-binding protein. Proc Natl Acad Sci U S A 90:1902-6
Krishnan, A V; Stathis, P; Permuth, S F et al. (1993) Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology 132:2279-86