scholarly journals Aspergillus fumigatus acetate utilisation impacts virulence traits and pathogenicity

2021 ◽  
Author(s):  
Laure NA Ries ◽  
Patricia Alves de Castro ◽  
Lilian P Silva ◽  
Clara Valero ◽  
Thaila Fernanda dos Reis ◽  
...  
Keyword(s):  
Carbon Source ◽  
Aspergillus Fumigatus ◽  
Carbon Sources ◽  
The Body ◽  
Regulatory Control ◽  
Fungal Virulence ◽  
Peripheral Tissues ◽  
Virulence Traits ◽  
Anti Fungal

Aspergillus fumigatus is a major opportunistic fungal pathogen of immunocompromised and immunocompetent hosts. To successfully establish an infection, A. fumigatus needs to use host carbon sources, such as acetate, present in the body fluids and peripheral tissues. However, utilisation of acetate as a carbon source by fungi in the context of infection has not been investigated. This work shows that acetate is metabolised via different pathways in A. fumigatus and that acetate utilisation is under the regulatory control of a transcription factor (TF), FacB. A. fumigatus acetate utilisation is subject to carbon catabolite repression (CCR), although this is only partially dependent on the TF and main regulator of CCR CreA. The available extracellular carbon source, in this case glucose and acetate, significantly affected A. fumigatus virulence traits such as secondary metabolite secretion and cell wall composition, with the latter having consequences for resistance to oxidative stress, to anti-fungal drugs and to human neutrophil-mediated killing. Furthermore, deletion of facB significantly impaired the in vivo virulence of A. fumigatus in both insect and mammalian models of invasive aspergillosis. This is the first report on acetate utilisation in A. fumigatus and this work further highlights the importance of available host-specific carbon sources in shaping fungal virulence traits and subsequent disease outcome, and a potential target for the development of anti-fungal strategies.

scholarly journals Aspergillus fumigatus Acetate Utilization Impacts Virulence Traits and Pathogenicity

mBio ◽  
2021 ◽  
Author(s):  
Laure Nicolas Annick Ries ◽  
Patricia Alves de Castro ◽  
Lilian Pereira Silva ◽  
Clara Valero ◽  
Thaila Fernanda dos Reis ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Fungal Pathogen ◽  
Carbon Sources ◽  
Body Fluids ◽  
Peripheral Tissues ◽  
Content Type ◽  
Virulence Traits ◽  
Acetate Utilization ◽  
Opportunistic Fungal Pathogen

Aspergillus fumigatus is an opportunistic fungal pathogen in humans. During infection, A. fumigatus is predicted to use host carbon sources, such as acetate, present in body fluids and peripheral tissues, to sustain growth and promote colonization and invasion.

The assimilation of different carbon sources in Candida albicans: Fitness and pathogenicity

2020 ◽  
Author(s):  
Bronwyn Lok ◽  
Mowaffaq Adam Ahmad Adam ◽  
Laina Zarisa Mohd Kamal ◽  
Nwakpa Anthony Chukwudi ◽  
Rosline Sandai ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Carbon Source ◽  
Fungal Infections ◽  
Carbon Sources ◽  
Surface Hydrophobicity ◽  
Vital Role ◽  
Infection Process ◽  
The Body ◽  
Mycelial Form ◽  
Cell Wall Biogenesis

Abstract Candida albicans is a commensal yeast commonly found on the skin and in the body. However, in immunocompromised individuals, the fungi could cause local and systemic infections. The carbon source available plays an important role in the establishment of C. albicans infections. The fungi's ability to assimilate a variety of carbon sources plays a vital role in its colonization, and by extension, its fitness and pathogenicity, as it often inhabits niches that are glucose-limited but rich in alternative carbon sources. A difference in carbon sources affect the growth and mating of C. albicans, which contributes to its pathogenicity as proliferation helps the fungi colonize its environment. The carbon source also affects its metabolism and signaling pathways, which are integral parts of the fungi's fitness and pathogenicity. As a big percentage of the carbon assimilated by C. albicans goes to cell wall biogenesis, the availability of different carbon sources will result in cell walls with variations in rigidity, adhesion, and surface hydrophobicity. In addition to the biofilm formation of the fungi, the carbon source also influences whether the fungi grow in yeast- or mycelial-form. Both forms play different roles in C. albicans’s infection process. A better understanding of the role of the carbon sources in C. albicans’s pathogenicity would contribute to more effective treatment solutions for fungal infections.

Carbon-source-dependent nitrogen regulation in Escherichia coli is mediated through glutamine-dependent GlnB signalling

Microbiology ◽  
2003 ◽  
Vol 149 (8) ◽  
pp. 2163-2172 ◽  
Author(s):  
Mani Maheswaran ◽  
Karl Forchhammer
Keyword(s):  
Escherichia Coli ◽  
Signal Transduction ◽  
Carbon Source ◽  
Glutamine Synthetase ◽  
Nitrogen Source ◽  
Carbon Sources ◽  
Nitrogen Status ◽  
Low Concentrations ◽  
Signal Transduction Proteins

The PII signal transduction proteins GlnB and GlnK are uridylylated/deuridylylated in response to the intracellular glutamine level, the primary signal of the cellular nitrogen status. Furthermore, GlnB was shown to be allosterically regulated by 2-oxoglutarate, and thus GlnB was suggested to integrate signals of the cellular carbon and nitrogen status. Receptors of GlnB signal transduction in Escherichia coli are the NtrB/NtrC two-component system and GlnE, an enzyme which adenylylates/deadenylylates glutamine synthetase. In this study, the authors investigated the effect of different carbon sources on the expression of the NtrC-dependent genes glnA and glnK and on the uridylylation status of GlnB and GlnK. With glutamine as nitrogen source, high levels of glnA and glnK expression were obtained when glucose was used as carbon source, but expression was strongly decreased when the cells were grown with poor carbon sources or when cAMP was present. This response correlated with the uridylylation status of GlnB, suggesting that the carbon/cAMP effect was mediated through GlnB uridylylation, a conclusion that was confirmed by mutants of the PII signalling pathway. When glutamine was replaced by low concentrations of ammonium as nitrogen source, neither glnAglnK expression nor GlnB uridylylation responded to the carbon source or to cAMP. Furthermore, glutamine synthetase could be rapidly adenylylated in vivo by the external addition of glutamine; however, this occurred only when cells were grown in the presence of cAMP, not in its absence. Together, these results suggest that poor carbon sources, through cAMP signalling, favour glutamine uptake. The cellular glutamine signal is then transduced by uridylyltransferase and GlnB to modulate NtrC-dependent gene expression.

scholarly journals Aca1 and Aca2, ATF/CREB Activators in Saccharomyces cerevisiae, Are Important for Carbon Source Utilization but Not the Response to Stress

2000 ◽  
Vol 20 (12) ◽  
pp. 4340-4349 ◽  
Author(s):  
M. Adelaida Garcia-Gimeno ◽  
Kevin Struhl
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Carbon Source ◽  
Target Genes ◽  
Carbon Sources ◽  
Biological Functions ◽  
Carbon Source Utilization ◽  
The Family ◽  
Response To Stress

ABSTRACT In Saccharomyces cerevisiae, the family of ATF/CREB transcriptional regulators consists of a repressor, Acr1 (Sko1), and two activators, Aca1 and Aca2. The AP-1 factor Gen4 does not activate transcription through ATF/CREB sites in vivo even though it binds these sites in vitro. Unlike ATF/CREB activators in other species, Aca1- and Aca2-dependent transcription is not affected by protein kinase A or by stress, and Aca1 and Aca2 are not required for Hog1-dependent salt induction of transcription through an optimal ATF/CREB site. Aca2 is important for a variety of biological functions including growth on nonoptimal carbon sources, and Aca2-dependent activation is modestly regulated by carbon source. Strains lacking Aca1 are phenotypically normal, but overexpression of Aca1 suppresses some defects associated with the loss of Aca2, indicating a functional overlap between Aca1 and Aca2. Acr1 represses transcription both by recruiting the Cyc8-Tup1 corepressor and by directly competing with Aca1 and Aca2 for target sites. Acr1 does not fully account for osmotic regulation through ATF/CREB sites, and a novel Hog1-dependent activator(s) that is not a bZIP protein is required for ATF/CREB site activation in response to high salt. In addition, Acr1 does not affect a number of phenotypes that arise from loss of Aca2. Thus, members of the S. cerevisiae ATF/CREB family have overlapping, but distinct, biological functions and target genes.

scholarly journals Identification and Characterization of a Novel Aspergillus fumigatus Rhomboid Family Putative Protease, RbdA, Involved in Hypoxia Sensing and Virulence

2016 ◽  
Vol 84 (6) ◽  
pp. 1866-1878 ◽  
Author(s):  
Yakir Vaknin ◽  
Falk Hillmann ◽  
Rossana Iannitti ◽  
Netali Ben Baruch ◽  
Hana Sandovsky-Losica ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Regulatory Element ◽  
Invasive Pulmonary Aspergillosis ◽  
Hyphal Growth ◽  
Fungal Virulence ◽  
Th17 Response ◽  
Content Type ◽  
Genes Encoding ◽  
Element Binding Protein

Aspergillus fumigatusis the most common pathogenic mold infecting humans and a significant cause of morbidity and mortality in immunocompromised patients. In invasive pulmonary aspergillosis,A. fumigatusspores are inhaled into the lungs, undergoing germination and invasive hyphal growth. The fungus occludes and disrupts the blood vessels, leading to hypoxia and eventual tissue necrosis. The ability of this mold to adapt to hypoxia is regulated in part by the sterol regulatory element binding protein (SREBP) SrbA and the DscA to DscD Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. Loss of the genes encoding these proteins results in avirulence. To identify novel regulators of hypoxia sensing, we screened theNeurospora crassagene deletion library under hypoxia and identified a novel rhomboid family protease essential for hypoxic growth. Deletion of theA. fumigatusrhomboid homologrbdAresulted in an inability to grow under hypoxia, hypersensitivity to CoCl2, nikkomycin Z, fluconazole, and ferrozine, abnormal swollen tip morphology, and transcriptional dysregulation—accurately phenocopying deletion ofsrbA. In vivo,rbdAdeletion resulted in increased sensitivity to phagocytic killing, a reduced inflammatory Th1 and Th17 response, and strongly attenuated virulence. Phenotypic rescue of the ΔrbdAmutant was achieved by expression and nuclear localization of the N terminus of SrbA, including its HLH domain, further indicating that RbdA and SrbA act in the same signaling pathway. In summary, we have identified RbdA, a novel putative rhomboid family protease inA. fumigatusthat mediates hypoxia adaptation and fungal virulence and that is likely linked to SrbA cleavage and activation.

scholarly journals Carbon Source-Dependent Phosphorylation of Hexokinase PII and Its Role in the Glucose-Signaling Response in Yeast

1998 ◽  
Vol 18 (5) ◽  
pp. 2940-2948 ◽  
Author(s):  
Francisca Randez-Gil ◽  
Pascual Sanz ◽  
Karl-Dieter Entian ◽  
Jose Antonio Prieto
Keyword(s):  
Carbon Source ◽  
Glucose Repression ◽  
Carbon Sources ◽  
Glucose Signaling ◽  
Regulatory Effects ◽  
Metabolic Signal ◽  
Signal Transductions ◽  
Mutant Cells

ABSTRACT The HXK2 gene is required for a variety of regulatory effects leading to an adaptation for fermentative metabolism inSaccharomyces cerevisiae. However, the molecular basis of the specific role of Hxk2p in these effects is still unclear. One important feature in order to understand the physiological function of hexokinase PII is that it is a phosphoprotein, since protein phosphorylation is essential in most metabolic signal transductions in eukaryotic cells. Here we show that Hxk2p exists in vivo in a dimeric-monomeric equilibrium which is affected by phosphorylation. Only the monomeric form appears phosphorylated, whereas the dimer does not. The reversible phosphorylation of Hxk2p is carbon source dependent, being more extensive on poor carbon sources such as galactose, raffinose, and ethanol. In vivo dephosphorylation of Hxk2p is promoted after addition of glucose. This effect is absent in glucose repression mutants cat80/grr1, hex2/reg1, andcid1/glc7. Treatment of a glucose crude extract fromcid1-226 (glc7-T152K) mutant cells with λ-phosphatase drastically reduces the presence of phosphoprotein, suggesting that CID1/GLC7 phosphatase together with its regulatory HEX2/REG1 subunit are involved in the dephosphorylation of the Hxk2p monomer. An HXK2 mutation encoding a serine-to-alanine change at position 15 [HXK2(S15A)] was to clarify the in vivo function of the phosphorylation of hexokinase PII. In this mutant, where the Hxk2 protein is unable to undergo phosphorylation, the cells could not provide glucose repression of invertase. Glucose induction ofHXT gene expression is also affected in cells expressing the mutated enzyme. Although we cannot rule out a defect in the metabolic state of the cell as the origin of these phenomena, our results suggest that the phosphorylation of hexokinase is essential in vivo for glucose signal transduction.

scholarly journals Anti-fungal activity of a novel triazole, PC1244, against emerging azole-resistant Aspergillus fumigatus and other species of Aspergillus

2019 ◽  
Vol 74 (10) ◽  
pp. 2950-2958 ◽  
Author(s):  
Thomas Colley ◽  
Cheshta Sharma ◽  
Alexandre Alanio ◽  
Genki Kimura ◽  
Leah Daly ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Geometric Mean ◽  
Gene Mutations ◽  
Aspergillus Tamarii ◽  
Potent Inhibition ◽  
Vitro Model ◽  
Immunocompromised Mice ◽  
Anti Fungal

Abstract Objectives The growing emergence of azole-resistant Aspergillus fumigatus strains worldwide is a major concern for current systemic antifungal treatment. Here we report antifungal activities of a novel inhaled triazole, PC1244, against a collection of multi-azole-resistant A. fumigatus strains. Methods MICs of PC1244 were determined for A. fumigatus carrying TR34/L98H (n = 81), TR46/Y121F/T289A (n = 24), M220 (n = 6), G54 (n = 11), TR53 (n = 1), TR463/Y121F/T289A (n = 2), G448S (n = 1), G432C (n = 1) and P216S (n = 1) resistance alleles originating from either India, the Netherlands or France. The effects of PC1244 were confirmed in an in vitro model of the human alveolus and in vivo in temporarily neutropenic, immunocompromised mice. Results PC1244 exhibited potent inhibition [geometric mean MIC (range), 1.0 mg/L (0.125 to >8 mg/L)] of growth of A. fumigatus strains carrying cyp51A gene mutations, showing much greater potency than voriconazole [15 mg/L (0.5 to >16 mg/L)], and an effect similar to those on other azole-susceptible Aspergillus spp. (Aspergillus flavus, Aspergillus terreus, Aspergillus tubingensis, Aspergillus nidulans, Aspergillus niger, Aspergillus nomius, Aspergillus tamarii) (0.18–1 mg/L). In TR34/L98H and TR46/Y121F/T289A A. fumigatus-infected in vitro human alveolus models, PC1244 achieved superior inhibition (IC50, 0.25 and 0.34 mg/L, respectively) compared with that of voriconazole (IC90, >3 mg/L and >10 mg/L, respectively). In vivo, once-daily intranasal administration of PC1244 (0.56–70 μg/mouse) to the A. fumigatus (AF91 with M220V)-infected mice reduced pulmonary fungal load and serum galactomannan more than intranasal posaconazole. Conclusions PC1244 has the potential to become a novel topical treatment of azole-resistant pulmonary aspergillosis.

Physiological disposition of d- and l-thyroxine in the rat

1959 ◽  
Vol 197 (5) ◽  
pp. 1021-1027 ◽  
Author(s):  
D. F. Tapley ◽  
F. F. Davidoff ◽  
W. B. Hatfield ◽  
J. E. Ross
Keyword(s):  
The Body ◽  
Optical Isomers ◽  
Half Time ◽  
Peripheral Tissues ◽  
Liver And Kidney ◽  
Physiological Disposition

A comparison was made of the distribution and excretion of the optical isomers of thyroxine in the rat. d-Thyroxine disappeared more rapidly from the blood and was concentrated to a greater extent in the liver and kidney than was l-thyroxine. The concentration of d-thyroxine in such peripheral tissues as muscle, brain and skin was much less than the concentration of l-thyroxine. This difference in distribution to the peripheral tissues was of such magnitude as to suggest a possible basis for the different activities of the two isomers observed in vivo. The half-time of d-thyroxine in the body (14 hr.) was significantly shorter than that of l-thyroxine (42 hr.).

scholarly journals Global Transcriptional Programs Reveal a Carbon Source Foraging Strategy byEscherichia coli

2005 ◽  
Vol 280 (16) ◽  
pp. 15921-15927 ◽  
Author(s):  
Mingzhu Liu ◽  
Tim Durfee ◽  
Julio E. Cabrera ◽  
Kai Zhao ◽  
Ding J. Jin ◽  
...  
Keyword(s):  
Carbon Source ◽  
Fluorescent Protein ◽  
Gene Activation ◽  
Carbon Sources ◽  
Growth Potential ◽  
Rrna Synthesis ◽  
Carbon Substrate ◽  
Protein Fusion ◽  
Substrate Quality

By exploring global gene expression ofEscherichia coligrowing on six different carbon sources, we discovered a striking genome transcription pattern: as carbon substrate quality declines, cells systematically increase the number of genes expressed. Gene induction occurs in a hierarchical manner and includes many factors for uptake and metabolism of better but currently unavailable carbon sources. Concomitantly, cells also increase their motility. Thus, as the growth potential of the environment decreases, cells appear to devote progressively more energy on the mere possibility of improving conditions. This adaptation is not what would be predicated by classic regulatory models alone. We also observe an inverse correlation between gene activation and rRNA synthesis suggesting that reapportioning RNA polymerase (RNAP) contributes to the expanded genome activation. Significant differences in RNAP distributionin vivo, monitored using an RNAP-green fluorescent protein fusion, from energy-rich and energy-poor carbon source cultures support this hypothesis. Together, these findings represent the integration of both substrate-specific and global regulatory systems, and may be a bacterial approximation to metazoan risk-prone foraging behavior.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

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