Metabolic Adaptation of Paracoccidioides brasiliensis in Response to in vitro Copper Deprivation

Petito, G. Timothy; Curcio, Juliana Santana de; Pereira, Maristela; Bailão, Alexandre Melo; Paccez, Juliano D.; Tristão, Gabriel Brum; Morais, Camila Oliveira Barbosa de; Souza, Marcelo José Raiol; Santos, Agenor Junior de Castro Moreira; Fontes, Wagner; Ricart, Carlos André Ornelas; Soares, Célia Maria de Almeida

doi:10.3389/fmicb.2020.01834

Cited by 11 publications

(9 citation statements)

References 57 publications

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“…Recent experiments in Paracoccidioides brasiliensis showed that copper deprivation has a major effect on fungal metabolism, but similar experiments have not been done in Coccidioides spp. [ 20 ]. In addition, a comparison of gene expression in C. posadasii spherules and an engineered chitinase deletion that does not endosporulate found that a major difference was the upregulation of iron and copper uptake genes, which is further evidence for the importance of iron and copper uptake for spherule and endospore formation [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing

Carlin

Beyhan

Peña

et al. 2021

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Coccidioides immitis and C. posadasii are dimorphic fungi that transform from mycelia with internal arthroconidia in the soil to a tissue form known as a spherule in mammals. This process can be recapitulated in vitro by increasing the temperature, CO2 and changing other culture conditions. In this study, we have analyzed changes in gene expression in mycelia and young and mature spherules. Genes that were highly upregulated in young spherules include a spherule surface protein and iron and copper membrane transporters. Genes that are unique to Coccidioides spp. are also overrepresented in this group, suggesting that they may be important for spherule differentiation. Enriched GO terms in young spherule upregulated genes include oxidation-reduction, response to stress and membrane proteins. Downregulated genes are enriched for transcription factors, especially helix–loop–helix and C2H2 type zinc finger domain-containing proteins, which is consistent with the dramatic change in transcriptional profile. Almost all genes that are upregulated in young spherules remain upregulated in mature spherules, but a small number of genes are differentially expressed in those two stages of spherule development. Mature spherules express more Hsp31 and amylase and less tyrosinase than young spherules. Some expression of transposons was detected and most of the differentially expressed transposons were upregulated in spherules.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing

Carlin

Beyhan

Peña

et al. 2021

JoF

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“…In addition to this function, AOX also decreases the rate of mitochondrial ROS formation ( Maxwell et al, 1999 ; Vishwakarma et al, 2015 ). In fungi, low copper availability was shown to be connected to impaired respiration (cytochrome c oxidase pathway) ( Joseph-Horne et al, 2001 ), which generally leads to ROS accumulation in the mitochondria; thus, positive regulation of alternative oxidase may compensate for this loss and minimize ROS formation, which was recently demonstrated in Paracoccidioides brasiliensis ( Petito et al, 2020 ) and in C. albicans , where copper starvation led to mitochondrial SOD1 repression and AOX induction enhanced cytochrome c oxidase activity ( Broxton and Culotta, 2016 ). NDH-2 is a rotenone-insensitive nonproton pumping oxidoreductase that catalyzes a reaction similar to that of complex I, but in contrast to complex I, NDH-2 is not involved in the generation of membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Copper Metabolism in Naegleria gruberi and Its Deadly Relative Naegleria fowleri

Ženíšková

Grechnikova

Šuták

2022

Front. Cell Dev. Biol.

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Although copper is an essential nutrient crucial for many biological processes, an excessive concentration can be toxic and lead to cell death. The metabolism of this two-faced metal must be strictly regulated at the cell level. In this study, we investigated copper homeostasis in two related unicellular organisms: nonpathogenic Naegleria gruberi and the “brain-eating amoeba” Naegleria fowleri. We identified and confirmed the function of their specific copper transporters securing the main pathway of copper acquisition. Adjusting to different environments with varying copper levels during the life cycle of these organisms requires various metabolic adaptations. Using comparative proteomic analyses, measuring oxygen consumption, and enzymatic determination of NADH dehydrogenase, we showed that both amoebas respond to copper deprivation by upregulating the components of the branched electron transport chain: the alternative oxidase and alternative NADH dehydrogenase. Interestingly, analysis of iron acquisition indicated that this system is copper-dependent in N. gruberi but not in its pathogenic relative. Importantly, we identified a potential key protein of copper metabolism of N. gruberi, the homolog of human DJ-1 protein, which is known to be linked to Parkinson’s disease. Altogether, our study reveals the mechanisms underlying copper metabolism in the model amoeba N. gruberi and the fatal pathogen N. fowleri and highlights the differences between the two amoebas.

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“…Members of the genus Paracoccidioides change their protein expression, and consequently their metabolism and virulence, as a response to physiological conditions induced in experimental settings, such as copper overload [ 34 ], copper deprivation [ 35 ], acetate availability [ 31 ], osmotic stress [ 36 ], among others. The present work demonstrates that P. brasiliensis and P. lutzii , when grown in vitro in the presence of L-DOPA, a substance potentially available for the fungus during parasitism, not only produce melanin, as already described [ 13 , 14 ], but also undergo metabolic shifts and present differential abundance of proteins previously related with fungal virulence.…”

Section: Discussionmentioning

confidence: 99%

“…The glyoxylate cycle is associated with virulence in some human pathogenic fungi [ 48 , 49 ], and isocitrate lyase appears to have a role in adhesion and colonization of host tissues by P. brasiliensis [ 50 ], reinforcing the role of L-DOPA in the virulence enhancement of this species. The enzymes enoyl-CoA hydratase (PADG_01209) and acyl-CoA dehydrogenase (PADG_02244) were more abundant in melanized Pb 18, indicating β-oxidation of fatty acids in this strain, which also occurs when acetate is available for fungal growth [ 31 ], and during copper deprivation [ 35 ] or experimental infection [ 51 ]. It was noteworthy that the enzymes related to ethanol production did not present differential abundance between melanized and non-melanized cells of both strains tested.…”

Section: Discussionmentioning

confidence: 99%

Beyond Melanin: Proteomics Reveals Virulence-Related Proteins in Paracoccidioides brasiliensis and Paracoccidioides lutzii Yeast Cells Grown in the Presence of L-Dihydroxyphenylalanine

Almeida‐Paes¹,

Almeida²,

Baeza

et al. 2020

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Species of the genus Paracoccidioides cause a systemic infection in human patients. Yeast cells of Paracoccidioides spp. produce melanin in the presence of L-dihydroxyphenylalanine and during infection, which may impact the pathogen’s survival in the host. To better understand the metabolic changes that occur in melanized Paracoccidioides spp. cells, a proteomic approach was performed to compare melanized and non-melanized Paracoccidioides brasiliensis and Paracoccidioides lutzii yeast cells. Melanization was induced using L-dihydroxyphenylalanine as a precursor, and quantitative proteomics were performed using reversed-phase nano-chromatography coupled to high-resolution mass spectrometry. When comparing melanized versus non-melanized cells, 1006 and 582 differentially abundant/detected proteins were identified for P. brasiliensis and P. lutzii, respectively. Functional enrichment and comparative analysis revealed 30 important KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in melanized P. brasiliensis and 18 in P. lutzii, while differentially abundant proteins from non-melanized cells from these species were involved in 21 and 25 enriched pathways, respectively. Melanized cells presented an abundance of additional virulence-associated proteins, such as phospholipase, proteases, superoxide dis-mutases, heat-shock proteins, adhesins, and proteins related to vesicular transport. The results suggest that L-dihydroxyphenylalanine increases the virulence of Paracoccidioides spp. through complex mechanisms involving not only melanin but other virulence factors as well.

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Metabolic Adaptation of Paracoccidioides brasiliensis in Response to in vitro Copper Deprivation

Cited by 11 publications

References 57 publications

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing

Copper Metabolism in Naegleria gruberi and Its Deadly Relative Naegleria fowleri

Beyond Melanin: Proteomics Reveals Virulence-Related Proteins in Paracoccidioides brasiliensis and Paracoccidioides lutzii Yeast Cells Grown in the Presence of L-Dihydroxyphenylalanine

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