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.
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| 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 |
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