Influence of 17β-Estradiol on Gene Expression of Paracoccidioides during Mycelia-to-Yeast Transition

Abstract

Background Paracoccidioides is the causative agent of paracoccidioidomycosis, a systemic mycosis endemic to Latin America. Infection is initiated by inhalation of conidia (C) or mycelial (M) fragments, which subsequently differentiate into yeast (Y). Epidemiological studies show a striking predominance of paracoccidioidomycosis in adult men compared to premenopausal women. In vitro and in vivo studies suggest that the female hormone (17β-estradiol, E2) regulates or inhibits M-or-C-to-Y transition. In this study we have profiled transcript expression to understand the molecular mechanism of how E2 inhibits M-to-Y transition.MethodologyWe assessed temporal gene expression in strain Pb01 in the presence or absence of E2 at various time points through 9 days of the M-to-Y transition using an 11,000 element random-shear genomic DNA microarray and verified the results using quantitative real time-PCR. E2-regulated clones were sequenced to identify genes and biological function.Principal FindingsE2-treatment affected gene expression of 550 array elements, with 331 showing up-regulation and 219 showing down-regulation at one or more time points (p≤0.001). Genes with low expression after 4 or 12 h exposure to E2 belonged to pathways involved in heat shock response (hsp90 and hsp70), energy metabolism, and several retrotransposable elements. Y-related genes, α-1,3-glucan synthase, mannosyltransferase and Y20, demonstrated low or delayed expression in E2-treated cultures. Genes potentially involved in signaling, such as palmitoyltransferase (erf2), small GTPase RhoA, phosphatidylinositol-4-kinase, and protein kinase (serine/threonine) showed low expression in the presence of E2, whereas a gene encoding for an arrestin domain-containing protein showed high expression. Genes related to ubiquitin-mediated protein degradation, and oxidative stress response genes were up-regulated by E2.ConclusionThis study characterizes the effect of E2 at the molecular level on the inhibition of the M-to-Y transition and is indicative that the inhibitory actions of E2 may be working through signaling genes that regulate dimorphism.

Shrinking Daughters: Rlm1-Dependent G1/S Checkpoint MaintainsSaccharomyces cerevisiaeDaughter Cell Size and Viability

“…Indeed, cell-wall synthesis genes are strongly induced in the pathogenic form relative to the filamentous form (Tavares et al 2015). Furthermore, Paracoccidioides infections occur in women much less frequently than in men, and one mechanism proposed for this gender-specific difference is that estrogen inhibits the CWI pathway/cell-wall synthesis (Shankar et al 2011;Tavares et al 2015). For this reason, antifungal drugs that inhibit formation or maintenance of rlm1D satellitegroup formation may be candidates for treatment of Paracoccidioides infections.…”

Paracoccidioides Species Complex: Ecology, Phylogeny, Sexual Reproduction, and Virulence

“…These adaptations may be indispensable for fungal virulence upon infection [25]. In contrast, some HSP genes are down-regulated when mycelia cells are incubated in vitro with estradiol or human female serum, in some part explaining the predominance of the disease in adult males [26]. The ability of fungal cells to adhere to host cells is also vital for the initial steps of the infection process.…”

Important aspects of oral paracoccidioidomycosis–a literature review

“…Women have a significantly lower prevalence of paracoccidioidomycosis, where they are protected against P. brasiliensis by the female hormone 17‐β‐estradiol. The interaction of this hormone with the receptor in the cytosol of the fungus prevents its transition from mycelium to yeast, which blocks the disease onset 11,61,62 . In these cases, the estradiol mechanism of action can be related to the modulation of the expression of genes that regulate fungal dimorphism, determining features such as cell wall maintenance and remodelling, energy metabolism and fungal response to temperature changes, among others 61 …”