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.
Highlights
Paracoccidioides is a thermally dimorphic fungus that is the etiological agent of paracoccidioidomycosis (PCM) [1]
This 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
Assessment of the molecular, phylogenetic analysis, and morphological characteristics of numerous isolates of Paracoccidioides has resulted in the differentiation of the genus into two species, P. brasiliensis and P. lutzii, the latter recently proposed as the new species comprised of the Pb01-like isolates [2]
Summary
Paracoccidioides is a thermally dimorphic fungus that is the etiological agent of paracoccidioidomycosis (PCM) [1]. The temperature of 37uC triggers its dimorphism in the host or in culture, which results in changes in cellular and cell wall constituents [5,6] Genomic approaches, such as EST (expressed sequence tag) analysis or suppression subtraction hybridization, and cDNA or gDNA microarrays have been used to identify differentially expressed genes in each morphological phase, during M-or-C-to-Y transition, or during host-pathogen interaction [7,8,9,10,11,12,13,14,15,16,17,18,19]. In this study we have profiled transcript expression to understand the molecular mechanism of how E2 inhibits M-to-Y transition
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