Relationship of progesterone- and estradiol-binding proteins in Coccidioides immitis to coccidioidal dissemination in pregnancy

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Abstract
Pregnancy is a major risk factor for coccidioidal dissemination. Because rates of Coccidioides immitis growth and endospore release are stimulated in vitro by levels of unbound progesterone and 17 beta-estradiol that are achievable, in vivo, in the sera of pregnant women (i.e., 10(-9) to 10(-8) M), a specific-hormone-binding system in C. immitis was sought. Fungal cytosols were incubated with tritiated steroids plus or minus radioinert steroids to identify specific binding systems. All five strains of C. immitis tested exhibited specific saturable binding for progestin, estrogen, androgen, and (to a lesser extent) corticosterone and glucocorticoid hormone classes. Only low or inconsistent estrogen or androgen binding was found in Blastomyces dermatitidis and Torulopsis glabrata. Cryptococcus neoformans, Paracoccidioides brasiliensis, and non-albicans Candida species showed no binding. Scatchard analysis of progestin and estrogen binding in C. immitis revealed a high-capacity, low-affinity binding system that was unaffected by RNase and DNase, but 40 to 60% degraded by trypsin or heating. Ammonium sulfate precipitation resolved a high-affinity, low-capacity binding system (Kd = 1.24 X 10(-9) to 3.60 X 10(-8) M; number of binding sites = 0.014 to 0.20 pmol/mg of protein). The Kd of this system is sufficient to compete for unbound hormone in the sera of pregnant women. The high-capacity, low-affinity system may serve as a repository for hormone before its attachment to the specific binder. These studies suggest that the effects of nanomolar concentrations of sex hormones on C. immitis may be mediated by a specific cytosol protein-binding system and that stimulatory events observed in vitro may have relevance for the mechanism of coccidioidal dissemination in pregnancy.