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Glucanase Induces Filamentation of the Fungal Pathogen Candida albicans  [PDF]
Hongbin Xu, Clarissa J. Nobile, Anna Dongari-Bagtzoglou
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063736
Abstract: Candida albicans is the most common human fungal pathogen. Many organisms, including C. albicans, secrete glucanases under different environmental conditions. Here, we report a novel role for beta-1, 3- glucanase in inducing Candida albicans to form filaments at 22°C and enhancing filamentation at 37°C in nutrient-rich medium. Quorum sensing, the efg1-signaling and cek1 MAP kinase pathways are involved in this process. Our data suggest that the natural antifungal agent beta–glucanase may support morphologic transformation of Candida albicans at a wide range of ambient temperatures.
Candida albicans Induces Selective Development of Macrophages and Monocyte Derived Dendritic Cells by a TLR2 Dependent Signalling  [PDF]
Alberto Yá?ez, Javier Megías, José-Enrique O'Connor, Daniel Gozalbo, M. Luisa Gil
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024761
Abstract: As TLRs are expressed by haematopoietic stem and progenitor cells (HSPCs), these receptors may play a role in haematopoiesis in response to pathogens during infection. We have previously demonstrated that in in vitro defined conditions inactivated yeasts and hyphae of Candida albicans induce HSPCs proliferation and differentiation towards the myeloid lineage by a TLR2/MyD88 dependent pathway. In this work, we showed that C. albicans invasive infection with a low virulence strain results in a rapid expansion of HSPCs (identified as LKS cells: Lin? c-Kit+ Sca-1+ IL-7Rα?), that reach the maximum at day 3 post-infection. This in vivo expansion of LKS cells in TLR2?/? mice was delayed until day 7 post- infection. Candidiasis was, as expected, accompanied by an increase in granulopoiesis and decreased lymphopoiesis in the bone marrow. These changes were more pronounced in TLR2?/? mice correlating with their higher fungal burden. Accordingly, emigration of Ly6Chigh monocytes and neutrophils to spleen was increased in TLR2?/? mice, although the increase in macrophages and inflammatory macrophages was completely dependent on TLR2. Similarly, we detected for the first time, in the spleen of C. albicans infected control mice, a newly generated population of dendritic cells that have the phenotype of monocyte derived dendritic cells (moDCs) that were not generated in TLR2?/? infected mice. In addition, C. albicans signalling through TLR2/MyD88 and Dectin-1 promotes in vitro the differentiation of Lin? cells towards moDCs that secrete TNF-α and are able to kill the microorganism. Therefore, our results indicate that during infection C. albicans can directly stimulate progenitor cells through TLR2 and Dectin-1 to generate newly formed inflammatory macrophages and moDCs that may fulfill an essential role in defense mechanisms against the pathogen.
The HOG Pathway Is Critical for the Colonization of the Mouse Gastrointestinal Tract by Candida albicans  [PDF]
Daniel Prieto, Elvira Román, Inês Correia, Jesus Pla
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087128
Abstract: The opportunistic pathogen Candida albicans is a frequent inhabitant of the human gastrointestinal tract where it usually behaves as a harmless commensal. In this particular niche, it needs to adapt to the different micro environments that challenge its survival within the host. In order to determine those factors involved in gut adaptation, we have used a gastrointestinal model of colonization in mouse to trace the behaviour of fungal cells. We have developed a genetic labelling system based on the complementary spectral properties of the fluorescent proteins GFP and a new C. albicans codon-adapted RFP (dTOM2) that allow a precise quantification of the fungal population in the gut via standard in vitro cultures or flow cytometry. This methodology has allowed us to determine the role of the three MAP kinase pathways of C. albicans (mediated by the MAPK Mkc1, Cek1 or Hog1) in mouse gut colonization via competitive assays with MAPK pathway mutants and their isogenic wild type strain. This approach reveals the signalling through HOG pathway as a critical factor influencing the establishment of C. albicans in the mouse gut. Less pronounced effects for mkc1 or cek1 mutants were found, only evident after 2–3 weeks of colonization. We have also seen that hog1 mutants is defective in adhesion to the gut mucosa and sensitive to bile salts. Finally, we have developed a genetic strategy for the in vivo excision (tetracycline-dependent) of any specific gene during the course of colonization in this particular niche, allowing the analysis of its role during gut colonization.
Modelling the Regulation of Thermal Adaptation in Candida albicans, a Major Fungal Pathogen of Humans  [PDF]
Michelle D. Leach, Katarzyna M. Tyc, Alistair J. P. Brown, Edda Klipp
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032467
Abstract: Eukaryotic cells have evolved mechanisms to sense and adapt to dynamic environmental changes. Adaptation to thermal insults, in particular, is essential for their survival. The major fungal pathogen of humans, Candida albicans, is obligately associated with warm-blooded animals and hence occupies thermally buffered niches. Yet during its evolution in the host it has retained a bona fide heat shock response whilst other stress responses have diverged significantly. Furthermore the heat shock response is essential for the virulence of C. albicans. With a view to understanding the relevance of this response to infection we have explored the dynamic regulation of thermal adaptation using an integrative systems biology approach. Our mathematical model of thermal regulation, which has been validated experimentally in C. albicans, describes the dynamic autoregulation of the heat shock transcription factor Hsf1 and the essential chaperone protein Hsp90. We have used this model to show that the thermal adaptation system displays perfect adaptation, that it retains a transient molecular memory, and that Hsf1 is activated during thermal transitions that mimic fever. In addition to providing explanations for the evolutionary conservation of the heat shock response in this pathogen and the relevant of this response to infection, our model provides a platform for the analysis of thermal adaptation in other eukaryotic cells.
Transcriptional Regulation of Carbohydrate Metabolism in the Human Pathogen Candida albicans  [PDF]
Christopher Askew,Adnane Sellam,Elias Epp,Hervé Hogues,Alaka Mullick,André Nantel,Malcolm Whiteway
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000612
Abstract: Glycolysis is a metabolic pathway that is central to the assimilation of carbon for either respiration or fermentation and therefore is critical for the growth of all organisms. Consequently, glycolytic transcriptional regulation is important for the metabolic flexibility of pathogens in their attempts to colonize diverse niches. We investigated the transcriptional control of carbohydrate metabolism in the human fungal pathogen Candida albicans and identified two factors, Tye7p and Gal4p, as key regulators of glycolysis. When respiration was inhibited or oxygen was limited, a gal4tye7 C. albicans strain showed a severe growth defect when cultured on glucose, fructose or mannose as carbon sources. The gal4tye7 strain displayed attenuated virulence in both Galleria and mouse models as well, supporting the connection between pathogenicity and metabolism. Chromatin immunoprecipitation coupled with microarray analysis (ChIP-CHIP) and transcription profiling revealed that Tye7p bound the promoter sequences of the glycolytic genes and activated their expression during growth on either fermentable or non-fermentable carbon sources. Gal4p also bound the glycolytic promoter sequences and activated the genes although to a lesser extent than Tye7p. Intriguingly, binding and activation by Gal4p was carbon source-dependent and much stronger during growth on media containing fermentable sugars than on glycerol. Furthermore, Tye7p and Gal4p were responsible for the complete induction of the glycolytic genes under hypoxic growth conditions. Tye7p and Gal4p also regulated unique sets of carbohydrate metabolic genes; Tye7p bound and activated genes involved in trehalose, glycogen, and glycerol metabolism, while Gal4p regulated the pyruvate dehydrogenase complex. This suggests that Tye7p represents the key transcriptional regulator of carbohydrate metabolism in C. albicans and Gal4p provides a carbon source-dependent fine-tuning of gene expression while regulating the metabolic flux between respiration and fermentation pathways.
Candida albicans isolated from human fungaemia induces apoptosis in an experimental endocarditis model
Hernández-Ca?averal, Iván;Becerra, Gerardo;Jiménez-Cordero, Alberto;Michel, Jean-Baptiste;Plascencia, Arturo;Domínguez-Hernández, Miguel;
Memórias do Instituto Oswaldo Cruz , 2009, DOI: 10.1590/S0074-02762009000600006
Abstract: candida albicans is the most common fungal pathogen known to cause endovascular infections, such as vascular catheter sepsis, infections of vascular prostheses and infective endocarditis. a c. albicans isolate was used to determine the apoptotic potential of the fungus in a rat endocarditis model. this study confirms the ability of c. albicans to induce apoptosis in myocardial tissue.
A genetic code alteration generates a proteome of high diversity in the human pathogen Candida albicans
Ana C Gomes, Isabel Miranda, Raquel M Silva, Gabriela R Moura, Benjamin Thomas, Alexandre Akoulitchev, Manuel AS Santos
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-10-r206
Abstract: Here we used an unusual decoding of leucine CUG codons as serine in the main human fungal pathogen Candida albicans to elucidate the global impact of genetic code alterations on the proteome. We show that C. albicans decodes CUG codons ambiguously and tolerates partial reversion of their identity from serine back to leucine on a genome-wide scale.Such codon ambiguity expands the proteome of this human pathogen exponentially and is used to generate important phenotypic diversity. This study highlights novel features of C. albicans biology and unanticipated roles for codon ambiguity in the evolution of the genetic code.Since the elucidation of the genetic code in the 1960s, 24 alterations in codon identity have been recorded in prokaryotic and eukaryotic translation systems. These alterations involve redefinition of identity of both sense and nonsense codons and codon unassignment (codons vanished from genomes) [1]. Furthermore, artificial expansion of the genetic code to incorporate non-natural amino acids [2-4] and natural incorporation of selenocysteine (Sec; 21st amino acid) and pyrrolysine (22nd amino acid) have also been reported [5,6]. Sec is incorporated in both prokaryotic and eukaryotic selenoproteins through reprogramming of UGA stop codons by novel translation elongation factors (selenoprotein translation factor B prokaryotes, elongation factor [EF]-Sec, and selenium-binding protein 2 eukaryotes), a new tRNA (tRNASec), and a Sec mRNA insertion element [7]. L-pyrrolysine insertion occurs in the archeon Methanosarcina barkeri through reprogramming of the UAG stop codon by a pyrrolysine insertion sequence in the methylamine methyltransferase mRNA [8]. The flexibility of the genetic code is further exemplified by the absence of glutamine and asparagine aminoacyl-tRNA synthetases in several mitochondria and archaeal and bacterial species. In those particular cases, aminoacylation of tRNAGln and tRNAAsn is accomplished by an ATP-dependent transamidation reaction
PKC Signaling Regulates Drug Resistance of the Fungal Pathogen Candida albicans via Circuitry Comprised of Mkc1, Calcineurin, and Hsp90  [PDF]
Shantelle L. LaFayette,Cathy Collins,Aimee K. Zaas,Wiley A. Schell,Marisol Betancourt-Quiroz,A. A. Leslie Gunatilaka,John R. Perfect,Leah E. Cowen
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001069
Abstract: Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to life-threatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections.
Rac1 Dynamics in the Human Opportunistic Fungal Pathogen Candida albicans  [PDF]
Romain Vauchelles,Danièle Stalder,Thomas Botton,Robert A. Arkowitz,Martine Bassilana
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015400
Abstract: The small Rho G-protein Rac1 is highly conserved from fungi to humans, with approximately 65% overall sequence identity in Candida albicans. As observed with human Rac1, we show that C. albicans Rac1 can accumulate in the nucleus, and fluorescence recovery after photobleaching (FRAP) together with fluorescence loss in photobleaching (FLIP) studies indicate that this Rho G-protein undergoes nucleo-cytoplasmic shuttling. Analyses of different chimeras revealed that nuclear accumulation of C. albicans Rac1 requires the NLS-motifs at its carboxyl-terminus, which are blocked by prenylation of the adjacent cysteine residue. Furthermore, we show that C. albicans Rac1 dynamics, both at the plasma membrane and in the nucleus, are dependent on its activation state and in particular that the inactive form accumulates faster in the nucleus. Heterologous expression of human Rac1 in C. albicans also results in nuclear accumulation, yet accumulation is more rapid than that of C. albicans Rac1. Taken together our results indicate that Rac1 nuclear accumulation is an inherent property of this G-protein and suggest that the requirements for its nucleo-cytoplasmic shuttling are conserved from fungi to humans.
Differentiation between Candida albicans and Candida dubliniensis using hypertonic Sabouraud broth and tobacco agar
Silveira-Gomes, Fabíola;Sarmento, Dayse Nogueira;Espírito-Santo, Elaine Patrícia Tavares do;Souza, Nádia de Oliveira;Pinto, Thifany Mendes;Marques-da-Silva, Silvia Helena;
Revista da Sociedade Brasileira de Medicina Tropical , 2011, DOI: 10.1590/S0037-86822011000400011
Abstract: introduction: opportunistic fungal infections in immunocompromised hosts are caused by candida species, and the majority of such infections are due to candida albicans. however, the emerging pathogen candida dubliniensis demonstrates several phenotypic characteristics in common with c. albicans, such as production of germ tubes and chlamydospores, calling attention to the development of stable resistance to fluconazole in vitro. the aim of this study was to evaluate the performance of biochemistry identification in the differentiating between c. albicans and c. dubliniensis, by phenotyping of yeast identified as c. albicans. methods: seventy-nine isolates identified as c. albicans by the api system id 32c were grown on sabouraud dextrose agar at 30°c for 24-48h and then inoculated on hypertonic sabouraud broth and tobacco agar. results: our results showed that 17 (21.5%) isolates were growth-inhibited on hypertonic sabouraud broth, a phenotypic trait inconsistent with c. albicans in this medium. however, the results observed on tobacco agar showed that only 9 (11.4%) of the growth-inhibited isolates produced characteristic colonies of c. dubliniensis (rough colonies, yellowish-brown with abundant fragments of hyphae and chlamydospores). conclusions: the results suggest that this method is a simple tool for screening c. albicans and non-albicans yeast and for verification of automated identification.
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