Upregulation of glyoxylate cycle genes upon<i>Paracoccidioides brasiliensis</i>internalization by murine macrophages and<i>in vitro</i>nutritional stress condition

Derengowski, Lorena S; Tavares, Aldo Henrique; Silva, S.; Procópio, Luciano; Felipe, Maria Sueli Soares; Silva-Pereira, Ildinete

doi:10.1080/13693780701670509

Cited by 50 publications

(46 citation statements)

References 44 publications

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“…The activation of the glyoxylate cycle is another important adaptation of many intracellular pathogens to the phagosomal microenvironment (34,35,43). Consistent with those observations, our results showed strong activation of the expression of its two regulatory enzymes, isocitrate lyase (Icl) and malate synthase (Mls), upon interaction of C. neoformans with both amoebae and macrophages.…”

Section: Gene Functional Categories (I) Genes Related To the Transposupporting

confidence: 79%

The Transcriptional Response of Cryptococcus neoformans to Ingestion by Acanthamoeba castellanii and Macrophages Provides Insights into the Evolutionary Adaptation to the Mammalian Host

et al. 2013

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Virulence of Cryptococcus neoformans for mammals, and in particular its intracellular style, was proposed to emerge from evolutionary pressures on its natural environment by protozoan predation, which promoted the selection of strategies that allow intracellular survival in macrophages. In fact, Acanthamoeba castellanii ingests yeast cells, which then can replicate intracellularly. In addition, most fungal factors needed to establish infection in the mammalian host are also important for survival within the amoeba. To better understand the origin of C. neoformans virulence, we compared the transcriptional profile of yeast cells internalized by amoebae and murine macrophages after 6 h of infection. Our results showed 656 and 293 genes whose expression changed at least 2-fold in response to the intracellular environments of amoebae and macrophages, respectively. Among the genes that were found in both groups, we focused on open reading frame (ORF) CNAG_05662, which was potentially related to sugar transport but had no determined biological function. To characterize its function, we constructed a mutant strain and evaluated its ability to grow on various carbon sources. The results showed that this gene, named PTP1 (polyol transporter protein 1), is involved in the transport of 5-and 6-carbon polyols such as mannitol and sorbitol, but its presence or absence had no effect on cryptococcal virulence for mice or moth larvae. Overall, these results are consistent with the hypothesis that the capacity for mammalian virulence originated from fungus-protozoan interactions in the environment and provide a better understanding of how C. neoformans adapts to the mammalian host.

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Section: Gene Functional Categories (I) Genes Related To the Transposupporting

confidence: 79%

The Transcriptional Response of Cryptococcus neoformans to Ingestion by Acanthamoeba castellanii and Macrophages Provides Insights into the Evolutionary Adaptation to the Mammalian Host

et al. 2013

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“…In this regard, it has been reported that, upon phagocytosis, there is a shift from fermentative to nonfermentative metabolism in intracellular pathogens, which may use two-carbon compounds from fatty acid degradation for energy production via the glyoxylate cycle (2,13,19,32,33,62). Indeed, the upregulation of genes from the glyoxylate cycle has been reported to occur during the M-to-Y differentiation of P. brasiliensis in culture medium (11,12,17,48) and upon the internalization of P. brasiliensis by murine macrophages (9,70). Additionally, nutritional stress conditions have been observed to influence the expression levels of the glyoxylate cycle-related genes of cultured yeast cells (9).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the upregulation of genes from the glyoxylate cycle has been reported to occur during the M-to-Y differentiation of P. brasiliensis in culture medium (11,12,17,48) and upon the internalization of P. brasiliensis by murine macrophages (9,70). Additionally, nutritional stress conditions have been observed to influence the expression levels of the glyoxylate cycle-related genes of cultured yeast cells (9). In this regard, the upregulation of Pbaox during the first hours of Mto-Y differentiation and during the exponential growth of the yeast form could be associated with fatty acid degradation.…”

Section: Discussionmentioning

confidence: 99%

Involvement of an Alternative Oxidase in Oxidative Stress and Mycelium-to-Yeast Differentiation in Paracoccidioides brasiliensis

et al. 2011

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Paracoccidioides brasiliensis is a thermodimorphic human pathogenic fungus that causes paracoccidioidomycosis (PCM), which is the most prevalent systemic mycosis in Latin America. Differentiation from the mycelial to the yeast form (M-to-Y) is an essential step for the establishment of PCM. We evaluated the involvement of mitochondria and intracellular oxidative stress in M-to-Y differentiation. M-to-Y transition was delayed by the inhibition of mitochondrial complexes III and IV or alternative oxidase (AOX) and was blocked by the association of AOX with complex III or IV inhibitors. The expression of P. brasiliensis aox (Pbaox) was developmentally regulated through M-to-Y differentiation, wherein the highest levels were achieved in the first 24 h and during the yeast exponential growth phase; Pbaox was upregulated by oxidative stress. Pbaox was cloned, and its heterologous expression conferred cyanide-resistant respiration in Saccharomyces cerevisiae and Escherichia coli and reduced oxidative stress in S. cerevisiae cells. These results reinforce the role of PbAOX in intracellular redox balancing and demonstrate its involvement, as well as that of other components of the mitochondrial respiratory chain complexes, in the early stages of the M-to-Y differentiation of P. brasiliensis.Paracoccidioides brasiliensis, which is a thermally dimorphic fungus, is the etiological agent of paracoccidioidomycosis (PCM), which is the most prevalent human systemic mycosis in Latin America (5, 52) and affects almost 10 million individuals in Latin America (54). It is acquired by the inhalation of airborne microconidia, which reach the pulmonary alveolar epithelium and transform into the pathogenic yeast form (52,54,59). The human form of PCM that is caused by this fungus is characterized by a range of clinical manifestations, ranging from asymptomatic forms to severe, disseminated, and often fatal disease. Usually, fibrosis sequelae in the affected organs may interfere with the well-being of the patient (50).During infection, thermodimorphic fungi, such as Histoplasma capsulatum, Blastomyces dermatitidis, and P. brasiliensis, differentiate from a mycelial into a pathogenic yeast form, a transition that can also be induced (in vitro) by temperature changes from between 23 and 26°C to between 35 and 37°C. In addition, these pathogens are often subjected to significant environmental stresses, including exposure to the reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are produced by the host cells (6,27,45).Elevated sublethal temperatures (thermal stress or heat shock) increase ROS generation and oxidative damage in a variety of eukaryotic cells (16,49,60,73). Mitochondria are the primary intracellular sources of ROS, which are generated in respiratory chain complexes I and III and can damage biomolecules, such as nucleic acids, lipids, and proteins (20)(21)(22). In order to control ROS levels, cells employ diverse detoxification mechanisms, including superoxide dismutase, catalase, the glutathione/thioredoxin...

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“…RT-PCR analysis showed that transcript levels of the ICL and MS genes in this fungus increased following phagocytosis by murine macrophages (Derengowski et al, 2008). Penicillium marneffei is a dimorphic fungus that can cause systemic mycosis in humans.…”

Section: Other Fungal Pathogensmentioning

confidence: 99%

Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis

2009

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The glyoxylate cycle is an anaplerotic pathway of the tricarboxylic acid (TCA) cycle that allows growth on C 2 compounds by bypassing the CO 2 -generating steps of the TCA cycle. The unique enzymes of this route are isocitrate lyase (ICL) and malate synthase (MS). ICL cleaves isocitrate to glyoxylate and succinate, and MS converts glyoxylate and acetyl-CoA to malate. The end products of the bypass can be used for gluconeogenesis and other biosynthetic processes. The glyoxylate cycle occurs in Eukarya, Bacteria and Archaea. Recent studies of ICL-and MS-deficient strains as well as proteomic and transcriptional analyses show that these enzymes are often important in human, animal and plant pathogenesis. These studies have extended our understanding of the metabolic pathways essential for the survival of pathogens inside the host and provide a more complete picture of the physiology of pathogenic micro-organisms. Hopefully, the recent knowledge generated about the role of the glyoxylate cycle in virulence can be used for the development of new vaccines, or specific inhibitors to combat bacterial and fungal diseases.

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Upregulation of glyoxylate cycle genes uponParacoccidioides brasiliensisinternalization by murine macrophages andin vitronutritional stress condition

Cited by 50 publications

References 44 publications

The Transcriptional Response of Cryptococcus neoformans to Ingestion by Acanthamoeba castellanii and Macrophages Provides Insights into the Evolutionary Adaptation to the Mammalian Host

The Transcriptional Response of Cryptococcus neoformans to Ingestion by Acanthamoeba castellanii and Macrophages Provides Insights into the Evolutionary Adaptation to the Mammalian Host

Involvement of an Alternative Oxidase in Oxidative Stress and Mycelium-to-Yeast Differentiation in Paracoccidioides brasiliensis

Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis

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