Morphological heterogeneity of<i>Paracoccidioides brasiliensis</i>: relevance of the Rho-like GTPase<i>PbCDC42</i>

Conidia/mycelium-to-yeast transition of Paracoccidioides brasiliensis is a critical step for the establishment of paracoccidioidomycosis, a systemic mycosis endemic in Latin America. Thus, knowledge of the factors that mediate this transition is of major importance for the design of intervention strategies. So far, the only known pre-requisites for the accomplishment of the morphological transition are the temperature shift to 37°C and the availability of organic sulfur compounds. In this study, we investigated the auxotrophic nature to organic sulfur of the yeast phase of Paracoccidioides , with special attention to P. brasiliensis species. For this, we addressed the role of SconCp, the negative regulator of the inorganic sulfur assimilation pathway, in the dimorphism and virulence of this pathogen. We show that down-regulation of SCONC allows initial steps of mycelium-to-yeast transition in the absence of organic sulfur compounds, contrarily to the wild-type fungus that cannot undergo mycelium-to-yeast transition under such conditions. However, SCONC down-regulated transformants were unable to sustain yeast growth using inorganic sulfur compounds only. Moreover, pulses with inorganic sulfur in SCONC down-regulated transformants triggered an increase of the inorganic sulfur metabolism, which culminated in a drastic reduction of the ATP and NADPH cellular levels and in higher oxidative stress. Importantly, the down-regulation of SCONC resulted in a decreased virulence of P. brasiliensis, as validated in an in vivo model of infection. Overall, our findings shed light on the inability of P. brasiliensis yeast to rely on inorganic sulfur compounds, correlating its metabolism with cellular energy and redox imbalances. Furthermore, the data herein presented reveal SconCp as a novel virulence determinant of P. brasiliensis.

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“…brasiliensis and its degree of virulence, including CDC42 [26,32], GP43 [33-35], HAD32 [36] and AOX [37]. However, the research on P.…”

Section: Discussionmentioning

confidence: 99%

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

et al. 2013

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“…One of P. brasiliensis biological hallmarks is its particular temperature-dependent morphological dimorphism. This fungus switches from the environmental non-pathogenic mycelial/conidial form at ambient temperatures to the pathogenic multiple budding yeast form, with an high variability of cell sizes, when exposed to temperatures similar to those of the mammalian host [2], [3], [4]. The mechanism of infection by P. brasiliensis entails the inhalation of airborne conidia that, when in the lung and exposed to host temperatures, undergo a complex morphological switch to the pathogenic yeast form [1], [5].…”

Section: Introductionmentioning

confidence: 99%

TLR9 Activation Dampens the Early Inflammatory Response to Paracoccidioides brasiliensis, Impacting Host Survival

et al. 2013

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Background Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear.Methodology/Principal findingsWe used in vitro and in vivo models of infection by P. brasiliensis, comparing wild type and TLR9 deficient (−/−) mice, to assess the contribution of TLR9 on cytokine induction, phagocytosis and outcome of infection. We show that TLR9 recognizes either the yeast form or DNA from P. brasiliensis by stimulating the expression/production of pro-inflammatory cytokines by bone marrow derived macrophages, also increasing their phagocytic ability. We further show that TLR9 plays a protective role early after intravenous infection with P. brasiliensis, as infected TLR9−/− mice died at higher rate during the first 48 hours post infection than wild type mice. Moreover, TLR9−/− mice presented tissue damage and increased expression of several cytokines, such as TNF-α and IL-6. The increased pattern of cytokine expression was also observed during intraperitoneal infection of TLR9−/− mice, with enhanced recruitment of neutrophils. The phenotype of TLR9−/− hosts observed during the early stages of P. brasiliensis infection was reverted upon a transient, 48 hours post-infection, neutrophil depletion.Conclusions/SignificanceOur results suggest that TLR9 activation plays an early protective role against P. brasiliensis, by avoiding a deregulated type of inflammatory response associated to neutrophils that may lead to tissue damage. Thus modulation of TLR9 may be of interest to potentiate the host response against this pathogen.

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Paracoccidioides brasiliensis PS2: First Autochthonous Paracoccidioidomycosis Case Report in Rio de Janeiro, Brazil, and Literature Review

et al. 2016

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Paracoccidioidomycosis (PCM) is a systemic mycosis caused by pathogenic dimorphic fungi of the Paracoccidioides brasiliensis complex. It is the most important systemic mycosis in Latin America, mainly in Brazil. Despite its severity and high mortality rates, it is considered a neglected disease. Species within the genus Paracoccidioides present genetics and morphological variations with probable clinical, diagnostic and therapeutic consequences. In fact, there are a very small number of detailed case reports with molecular identification of these fungal agents. Here, it is reported a case of PCM due to Paracoccidioides brasiliensis PS2. Molecular identification of the isolate was performed by amplification and sequencing of the arf and gp43 genes. Clinical cases and strain reports with molecular identification in the literature are also reviewed. The case herein presented is the first autochthonous report of PCM due to Paracoccidioides brasiliensis PS2 species in the state of Rio de Janeiro, Brazil, an important endemic area. The patient presented a chronic pulmonary form of PCM and had a satisfactory response to sulfamethoxazole/trimethoprim although sequelae such as adrenal insufficiency and dysphonia were observed. This study may contribute to improve the knowledge about this severe disease, its causative cryptic species and their consequences to patients.

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Morphological heterogeneity ofParacoccidioides brasiliensis: relevance of the Rho-like GTPasePbCDC42

Cited by 4 publications

References 14 publications

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

P. brasiliensis Virulence Is Affected by SconC, the Negative Regulator of Inorganic Sulfur Assimilation

TLR9 Activation Dampens the Early Inflammatory Response to Paracoccidioides brasiliensis, Impacting Host Survival

Paracoccidioides brasiliensis PS2: First Autochthonous Paracoccidioidomycosis Case Report in Rio de Janeiro, Brazil, and Literature Review

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