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PubMed1977

Paracoccidioides brasiliensis: cell wall structure and virulence. A review.

Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis or South American blastomycosis. Many aspects of the disease and its agent are unknown. One of the most important factors regarding the infection and the host-parasite relationships seems to be the fungal cell wall whose biochemical aspects are reviewed here. Biochemical studies, done mainly by Kanetsuna et al., (21,22), have demonstrated that the yeastlike (Y) and the mycelial (M) forms have chitin as a common polysaccharide, with alpha-1, 3-glucan in the Y form and beta-1, 3-glucan in the M form. These polysaccharides are fibrillar and determine to some degree the fungal shape. Moreover, an amorphous galactomannan is found in the cell wall of the M form. This compound is responsible for the antigenic properties of the cell wall (1). Recent studies (30-33) suggest that the cell wall does not possess a stable chemical structure but a rather changing one, as a function of the environment in which the fungus is grown. At the same time, the cell wall composition seems to correlate with the degree of virulence of the particular strain. From these observations it may be deduced that the constituent polysaccharides of P. brasiliensis cell wall, play an important role in the active protection of the fungus against the defensive mechanisms of the host.

Antigens, Fungal↗

PubMed1996

Polyamines in growth and dimorphism of Paracoccidioides brasiliensis.

Putrescine and spermidine were the only polyamines found in Paracoccidioides brasiliensis, a dimorphic fungus pathogenic for humans. Free polyamines (putrescine > spermidine) increased during the first 24 h of yeast growth, with a second peak at 42 h, and also during the first 12 h of mycelium-to-yeast transition (spermidine > putrescine). Conjugated and bound polyamines were also quantified. 1, 4-Diamino-2-butanone decreased free putrescine and spermidine accumulation by inhibiting the activity of ornithine decarboxylase. The increase in free polyamines corresponds to bud emergence in yeast growth and to the mycelium-to-yeast transition of P. brasiliensis.

Ornithine Decarboxylase Inhibitors↗

PubMed1996

Inoculation experimental animals with Paracoccidioides brasiliensis strains: an attempt to reestablish the dimorphic process and variation in pathogenicity as a function of time of preservation under mineral oil.

In an attempt to reestablish the dimorphic process in strains of Paracoccidioides brasiliensis in the transition phase (Y reversible M) and to reisolate them, five strains in the transitional phase due to the long time of preservation under mineral oil and two strains in the yeast-like phase were inoculated into male albino rats. The animals were then studied for the presence of paracoccidioidomycotic granulomata. Of the seven strains inoculated, five caused granulomatous nodules in several organs of the animals and only two of these five strains, which had been preserved for the shortest period of time (9 years) were reisolated in culture. Two strains were unable to provoke infection, with no lesions detected in any organ. It is assumed that the long period of time during which the strains were left under oil favored the alteration of celt wall contents, leading to differences in pathogenicity.

Animals↗

PubMed1978

Effects of cyanein and ramihyphin A on the dimorphism of Paracoccidioides brasiliensis.

As a preliminary step in the study of dimorphism in Paracoccidioides brasiliensis, the effects of cyanein and ramihyphin A were studied. These antibiotics have been reported to induce morphological changes in fungi. The results obtained suggest that ramihyphin A induce swelling of hyphae while partially inhibiting Y leads to M transformation with the production of an incipient and swollen mycelium. Cyanein did not affect the mycelial morphology as did ramihyphin A. However, the Y leads to M transformation was inhibited and, also, the M leads to Y transformation was blocked with the production of a few yeast cells which were not released from the mycelium.

Antifungal Agents↗

PubMed1996

Ornithine decarboxylase in Paracoccidioides brasiliensis.

Ornithine decarboxylase in Paracoccidioides brasiliensis, a dimorphic human pathogenic fungus, was more active at 37 degrees C in the yeast phase and at 30 degrees C in the mycelial phase. In contrast to other fungal systems, yeast growth and mycelium-to-yeast transition in P. brasiliensis were accompanied by a high activity of ornithine decarboxylase at the onset of the budding process, the activity of which was inhibited by 1,4-diamino-2-butanone. The activity of ornithine decarboxylase remained at a basal level during vegetative growth of both the mycelial phase and the late stage of yeast phase, and also through the yeast-to-mycelium transition.

Enzyme Inhibitors↗

PubMed1998

Cytosolic neutral proteinases of Paracoccidioides brasiliensis.

Cytosolic proteinases were assayed in both morphological phases of Paracoccidioides brasiliensis. Preparations from the mycelial phase were more active in vitro than those from the yeast cells. Optimal proteinase activities for both phases occurred at pH's between 6.0 and 9.0, and at 45 degrees C. Gelatin-SDS-PAGE electrophoresis separated several bands (58-112 kDa) in mycelial preparations; a single band (70 kDa) was seen in yeast preparations. Enzymatic activities were inhibited by antipain, phenyl methyl sulfonyl fluoride (PMSF), and chymostatin, suggestive of serine proteinases. Partial inhibition of the mycelial enzymes by ethylene diamine tetraacetic acid (EDTA), 1,10-phenanthroline, and iodoacetamide, also suggested the presence of cysteine- and metallo-proteinases. The enzymatic activity increased in preparations extracted from yeast cells transforming to mycelia, and decreased in preparations obtained from the reverse process.

Antipain↗

PubMed1999

Influence of the genetic background on the pattern of lesions developed by resistant and susceptible mice infected with Paracoccidioides brasiliensis.

To compare the sequential evolution of lesions developed by resistant (A/Sn) and susceptible (B10.A) mice to Paracoccidioides brasiliensis infection we inoculated a virulent isolate of the fungus and collected the pancreas/peripancreatic omentum monthly (from 1 to 6 months) post infection. After fixation, tissue sections were stained by conventional methods for light microscopy to investigate the cellular composition, the extracellular matrix (ECM) patterns and the morphology of the yeasts in the lesions. In both strains, the fungal lesions were localized mostly in the omentum; a few lesions in the pancreatic parenchyma were observed, mostly in B10.A mice. In both strains, macrophages and plasmocytes were the predominant cells in all lesions, followed by neutrophils (PMN) and macrophages transformed into giant and epithelioid cells. Remarkable differences were observed between resistant and susceptible mice, specially related to the ECM structure of the granulomatous lesions. In A/Sn mice, from the 1st month on, the coexistence of two types of lesions was observed: one type showed a well-defined encapsulated nodule, constituted mainly of type I collagen. Neutrophils were abundant in areas of massive fungal destruction and few viable yeasts were observed. The other type showed residual characteristics, with sparse collagen deposits and presence of xantomatous-like macrophages, containing degenerated fungi. Such residual lesions predominated after the 2nd month and were the only type observed from the 4th month on, indicating the control of the infection. In B10.A mice, on the contrary, only one type of lesion was observed, showing less tendency to encapsulation and the formation of multiple small granulomatous foci, individualized by reticular type III collagen fibers. There were many plasmocytes in the periphery and large numbers of budding yeasts, with no evidence of fungal destruction. In the course of the infection the lesions progressively increased in number and size. Altogether, the comparative histopathological analysis demonstrates the influence of the genetic pattern of the host on the lesions developed by resistant and susceptible mice to P. brasiliensis infection.

Animals↗

PubMed2004

Identification of genes preferentially expressed in the pathogenic yeast phase of Paracoccidioides brasiliensis, using suppression subtraction hybridization and differential macroarray analysis.

Paracoccidioides brasiliensis, a thermodimorphic fungus, is the causative agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America. Pathogenicity appears to be intimately related to the dimorphic transition from the hyphal to the yeast form, which is induced by a shift from environmental temperature to the temperature of the mammalian host. Little information is available on the P. brasiliensis genes that are necessary during the pathogenic phase. We have therefore undertaken Suppression Subtraction Hybridization (SSH) and macroarray analyses with the aim of identifying genes that are preferentially expressed in the yeast phase. Genes identified by both procedures as being more highly expressed in the yeast phase are involved in basic metabolism, signal transduction, growth and morphogenesis, and sulfur metabolism. In order to test whether the observed changes in gene expression reflect the differences between the growth conditions used to obtain the two morphological forms rather than differences intrinsic to the cell types, we performed real-time RT-PCR experiments using RNAs derived from both yeast cells and mycelia that had been cultured at 37 degrees C and 26 degrees C in either complete medium (YPD or Sabouraud) or minimal medium. Twenty genes, including AGS1 (alpha-1,3-glucan synthase) and TSA1 (thiol-specific antioxidant), were shown to be more highly expressed in the yeast cells than in the hyphae. Although their levels of expression could be different in rich and minimal media, there was a general tendency for these genes to be more highly expressed in the yeast cells.

DNA, Complementary↗

PubMed2006

Transcriptome analysis and molecular studies on sulfur metabolism in the human pathogenic fungus Paracoccidioides brasiliensis.

The dimorphic pathogenic fungus Paracoccidioides brasiliensis can grow as a prototroph for organic sulfur as a mycelial (non-pathogenic) form, but it is unable to assimilate inorganic sulfur as a yeast (pathogenic) form. Temperature and the inability to assimilate inorganic sulfur are the single conditions known to affect P. brasiliensis mycelium-to-yeast (M-Y) dimorphic transition. For a comprehensive evaluation of genes that have their expression modulated during the M-Y transition in different culture media, we performed a large-scale analysis of gene expression using a microarray hybridization approach. The results of the present work demonstrate the use of microarray hybridization analysis to examine gene expression during the M-Y transition in minimal medium and compare these results with the M-Y transition in complete medium. Our results showed that about 95% of the genes in our microarray are mainly responding to the temperature trigger, independently of the media where the M-Y transition took place. As a preliminary step to understand the inorganic sulfur inability in P. brasiliensis yeast form, we decided to characterize the mRNA accumulation of several genes involved in different aspects of both organic and inorganic sulfur assimilation. Our results suggest that although P. brasiliensis cannot use inorganic sulfur as a single sulfur source to initiate both M-Y transition and Y growth, the fungus can somehow use both organic and inorganic pathways during these growth processes.

Base Sequence↗

PubMedDate not supplied

Morphological, biochemical and molecular approaches for comparing typical and atypical Paracoccidioides brasiliensis strains.

We evaluated the morphology of typical and atypical Paracoccidioides brasiliensis strains and the expression of its 43 kDa glycoprotein (GP43). Strains of P. brasiliensis preserved under mineral oil for long periods of time presented different morphological patterns on peptone, yeast-extract and glucose (PYG) agar. The intravenous inoculation in BALB/c mice confirmed that a strain bearing morphological alterations was non-virulent. In contrast, another strain also maintained under mineral oil but which did not exhibit such morphological dysfunction was as virulent as the well characterized Pb 339 and Pb 18 strains. The expression of the main antigen expressed by P. brasiliensis, GP43, was assessed in culture filtrates by western immunoblots. Typical and atypical strains were capable of secreting the glycoprotein, except strain Pb IOC 1059. The identity of the atypical strains was confirmed by PCR using specific primers for gp43, though the single PCR-fragment varied in size for the atypical strains. The PCR fragments from an atypical strain, Pb IOC 1210, and the typical Pb 339 and Pb IOC 3698 strains were sequenced and blasted to the gp43 gene from the Pb 18 strain (GenBank AY005429). These results ensured the identity of the atypical strains as P. brasiliensis, and suggested a relationship between the alteration of morphological differentiation and the virulence factor following storage under mineral oil.

Animals↗

PubMed2006

Epithelial cells treated with genistein inhibit adhesion and endocytosis of Paracoccidioides brasiliensis.

Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis, which although not formally considered an intracellular pathogen, can be internalized by epithelial cells in vitro and in vivo. The mechanisms used by P. brasiliensis to adhere to and invade non-professional phagocytes have not been identified. The signal-transduction networks, involving protein tyrosine kinase (PTK) and protein phosphatase activities, can modulate crucial events during fungal infections. In this study, the involvement of PTK has been investigated in P. brasiliensis adherence and invasion in mammalian epithelial cells. A significant inhibition of the fungal invasion occurred after the pre-treatment of the epithelial cells with genistein, a specific tyrosine kinase inhibitor, indicating that the tyrosine kinase pathway is involved in P. brasiliensis internalization. In contrast, when the fungus was treated, a slight (not significant) inhibition of PTK was observed, suggesting that PTK might not be the fungus' transduction signal pathway during the invasion process of epithelial cells. An intense PTK immunofluorescence labeling was observed in the periphery of the P. brasiliensis infected cells, little PTK labeling was found in both uninfected cells and yeast cells, at later infection times (8 and 24 h). Moreover, when the epithelial cells were treated with genistein and infected with P. brasiliensis, no labeling was observed, suggesting the importance of the PTK in the infectious process. These results suggest that PTK pathway participates in the transduction signal during the initial events of the adhesion and invasion processes of P. brasiliensis to mammalian epithelial cells.

Bacterial Adhesion↗

PubMed2006

Serological detection of antibodies against Paracoccidioides brasiliensis in dogs with leishmaniasis.

The aim of this study was to detect antibodies against Paracoccidioides brasiliensis in dogs seropositive and seronegative for leishmaniasis. Sera from 836 dogs (449 positive and 387 negative to leishmaniasis) were analysed by ELISA and the immunodiffusion test using gp43 and exoantigen, respectively. The analysis of the 836 serum samples by ELISA and the immunodiffusion test showed a positivity of 67.8 % and 7.3%, respectively, for P. brasiliensis infection. The dogs positive to leishmaniasis showed a higher reactivity to gp43 (79.9%) and exoantigen (12.7%) than the negative ones (54.0% and 1.0%, respectively). The higher reactivity to P. brasiliensis antigens may be due to cross-reactivity or a co-infection of dogs by Leishmania and P. brasiliensis. The lower correlation (0.187) observed between reactivity to gp43 and Leishmania antigen reinforces the latter hypothesis.

Animals↗

PubMed1991

The 43-kDa glycoprotein from the human pathogen Paracoccidioides brasiliensis and its deglycosylated form: excretion and susceptibility to proteolysis.

Biochemical properties of the concanavalin A-binding 43-kDa glycoprotein (gp43) of Paracoccidioides brasiliensis and its deglycosylated form were compared. Deglycosylation was achieved by treatment with trifluoromethanesulfonic acid, endoglycosidase H, N-glycanase, or metabolically, by growing cells with tunicamycin. The resulting antigen in all cases had Mr 38,000, and probably derived from the gp43 by loss of N-linked high-mannose oligosaccharide chains. The presence of galactopyranose units in the carbohydrate chains was suggested by antigen binding to peanut lectin. Pulse and chase experiments using [35S]methionine metabolic labeling of P. brasiliensis growing in the presence of tunicamycin showed that the N-linked chains of gp43 are not required for antigen secretion. The 38-kDa antigen was more susceptible than the native antigen to the action of papain and pronase, thus indicating a protective role of the carbohydrate moiety against proteolysis. Both forms are equally resistant to endogenous proteases at neutral pH. The gp43, itself, has a proteolytic activity at pH 5-6, but not at neutral pH. Deglycosylation with endoglycosidase H or tunicamycin preserved epitopes in the 38-kDa molecule reactive with (a) antibodies from patients with paracoccidioidomycosis, or rabbit immunized with the gp43 and (b) mouse monoclonal antibodies against the gp43 antigen. The present results provide a basis for the understanding of diagnostic reactions and fungal virulence involving the gp43 exocellular antigen of P. brasiliensis.

Antigens, Fungal↗

PubMed1983

Indirect fluorescent test for detection of anti-Paracoccidioides brasiliensis antibodies using coated bentonite particles as antigen.

An indirect fluorescent test was developed for detecting antibodies to Paracoccidioides brasiliensis using bentonite particles as antigen (Bent-IF). The bentonite particles were coated with P. brasiliensis polysaccharide antigen and tested with sera from paracoccidioidomycosis patients (36 sera), normal blood donors (32 sera) and patients with non-mycotic diseases (29 sera). The titres given by the positive sera were compared with those of complement fixation (CF), immunodiffusion (ID) and immunofluorescent test using yeast forms of the fungus as antigen (conventional-IF). All normal blood donors' sera gave a negative Bent-IF, conventional-IF, ID and CF tests. All paracoccidioidomycosis sera were reactive in conventional-IF and gave concordant results in Bent-IF. There was no correlation between CF and Bent-IF titres. 27.6% of sera from patients with non-mycotic diseases gave weak titres in both IF-tests. The present data indicate that the Bent-IF is a sensitive and simple serodiagnostic technique comparable with the conventional P. brasiliensis antibody test.

Antibodies, Fungal↗

PubMed1985

Granulomatous reaction induced by lipids isolated from Paracoccidioides brasiliensis.

The possibility that the histological responses produced in paracoccidioidomycosis might be attributed to lipid constituents of cells of Paracoccidioides brasiliensis was investigated. Charcoal particles coated with the lipid extract were prepared and the suspension inoculated intravenously into mice. The lung inflammation was characterized by an intense mononuclear and polymorphonuclear cell infiltrate surrounding the particles from two to eight days after inoculation. Fractionation of lipid extract by preparative thin-layer chromatography allowed the separation of several fractions and it was observed that fractions containing free fatty acids and triglycerides were the most active. The participation of an uncommon fatty acid eliciting an inflammatory reaction is discussed.

Animals↗

PubMedDate not supplied

Isolation and partial characterization of a Paracoccidioides brasiliensis 58 kDa extracellular glycoprotein which is recognized by human immune sera.

A novel 58 kDa antigenic determinant of the fungus Paracoccidioides brasiliensis was identified by enzyme-linked immunosorbent assay using a panel of species-specific murine monoclonal antibodies (MAbs). Western immunoblot analysis, deglycosylation studies and isoelectric focusing indicated that this 58 kDa antigen is a glycoprotein, with a pI of approximately 5.2. The molecule was purified from P. brasiliensis culture filtrate and yeast cytoplasmic antigens by membrane ultrafiltration, liquid isoelectric focusing and gel filtration; N-terminal amino acid sequence data revealed no substantial homology with known proteins. The presence of the antigen in the cytoplasm of both yeast and mycelial forms of the fungus was demonstrated when these MAbs were used as markers in immunofluorescence, immunoperoxidase and immunoalkaline phosphatase techniques to label P. brasiliensis in cryostat sections. These MAbs also recognized the cytoplasm of P. brasiliensis yeast forms in paraffin-embedded pathological specimens from human cases. A preparation of the 58 kDa component from yeast cytoplasmic antigen was reacted by Western immunoblotting with 26 different serum samples from paracoccidioidomycosis patients, and 81% of them recognized it.

Adult↗

PubMed1993

Identification of sialic acids on the cell surface of hyphae and yeast forms of the human pathogen Paracoccidioides brasiliensis.

Paracoccidioides brasiliensis, the agent of paracoccidioidomycosis, when grown in a synthetic medium, expresses at the cell surface of both yeast and mycelial forms acidic glycoconjugates containing N-acetylneuraminic acid units. Sialic acids were extracted using mild hydrolytic conditions, and were identified by thin-layer and gas chromatography, standard colorimetry, reaction with periodate-resorcinol and mass spectrometry. Their surface location was inferred from fluorescent-lectin (Limulus polyphemus agglutinin) binding to whole cells abrogated by previous treatment with neuraminidase. Expression of sialic acids on virulent yeast forms of P. brasiliensis (3.7 x 10(6) residues per cell) may inhibit fungal phagocytosis during early infection, when the immunological response is still being built up.

Cell Membrane↗

PubMed2005

Investigation of the role of complement and complement receptors in the modulation of B cell activation by a Paracoccidioides brasiliensis cell wall fraction.

F1 fraction from Paracoccidioides brasiliensis is a potent activator of the complement system. Considering that complement receptors CR1 and CR2 are involved in the regulation of B cell response, we evaluated the in vitro effect of the F1 in the activation of B lymphocytes, as well as the participation of complement receptors in this process. Murine splenocytes were cultured in order to evaluate the expression of CD40, CD45RB and CD69 on B lymphocyte, and IgG and IgM were quantified in the culture supernatant. F1 participated in the activation of B cells, showing a positive modulation effect on all markers analyzed. An increase in the production of IgG was detected in the supernatants when the opsonized F1 fraction was present. Complement receptor blockade with monoclonal antibodies led to a partial reduction in immunoglobulin secretion, suggesting that these receptors, especially CR2, play a role in modulating the function of B lymphocyte stimulated with the opsonized F1 fraction. These results may contribute for a better understanding of the B cell activation and differentiation processes in response to the F1 fraction from P. brasiliensis.

Animals↗