scholarly journals Rhb1 Regulates the Expression of Secreted Aspartic Protease 2 through the TOR Signaling Pathway in Candida albicans

2011 ◽  
Vol 11 (2) ◽  
pp. 168-182 ◽  
Author(s):  
Yu-Ting Chen ◽  
Chia-Ying Lin ◽  
Pei-Wen Tsai ◽  
Cheng-Yao Yang ◽  
Wen-Ping Hsieh ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Signaling Pathway ◽  
Virulence Factor ◽  
Nitrogen Availability ◽  
Target Genes ◽  
Small Gtpase ◽  
Aspartic Protease ◽  
Tor Signaling ◽  
Content Type

ABSTRACTCandida albicansis a major fungal pathogen in humans. InC. albicans, secreted aspartyl protease 2 (Sap2) is the most highly expressed secreted aspartic proteasein vitroand is a virulence factor. Recent research links the small GTPase Rhb1 toC. albicanstarget of rapamycin (TOR) signaling in response to nitrogen availability. The results of this study show that Rhb1 is related to cell growth through the control ofSAP2expression when protein is the major nitrogen source. This process involves various components of the TOR signaling pathway, including Tor1 kinase and its downstream effectors. TOR signaling not only controlsSAP2transcription but also affects Sap2 protein levels, possibly through general amino acid control. DNA microarray analysis identifies other target genes downstream of Rhb1 in addition toSAP2. These findings provide new insight into nutrients, Rhb1-TOR signaling, and expression ofC. albicansvirulence factor.

scholarly journals Distinct Roles of Candida albicans Drug Resistance Transcription FactorsTAC1,MRR1, andUPC2in Virulence

2013 ◽  
Vol 13 (1) ◽  
pp. 127-142 ◽  
Author(s):  
Andrea Lohberger ◽  
Alix T. Coste ◽  
Dominique Sanglard
Keyword(s):  
Candida Albicans ◽  
Target Genes ◽  
Negative Impact ◽  
Antifungal Drugs ◽  
Wild Type ◽  
Drug Pressure ◽  
Content Type ◽  
Negative Effect

ABSTRACTAzoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur inCandida albicansprincipally by overexpression of multidrug transporter geneCDR1,CDR2, orMDR1or by overexpression ofERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs)TAC1(involved in the control ofCDR1andCDR2),MRR1(involved in the control ofMDR1), andUPC2(involved in the control ofERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial toC. albicanssurvival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence ofC. albicansin the absence of the selective drug pressure. In this work, the effect of GOF mutations onC. albicansvirulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neitherTAC1norMRR1GOF mutations had a significant effect onC. albicansvirulence. In contrast, the presence of two hyperactiveUPC2alleles inC. albicansresulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate withUPC2hyperactive alleles was observed in competition experiments with the wild typein vivobut notin vitro. Interestingly,UPC2hyperactivity delayed filamentation ofC. albicansafter phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining theUPC2GOF mutation with another hyperactive TF did not compensate for the negative effect ofUPC2on virulence. In conclusion, among the major TFs involved in azole resistance, onlyUPC2had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

scholarly journals In VitroAnalyses of the Effects of Heparin and Parabens on Candida albicans Biofilms and Planktonic Cells

2011 ◽  
Vol 56 (1) ◽  
pp. 148-153 ◽  
Author(s):  
Marisa H. Miceli ◽  
Stella M. Bernardo ◽  
T. S. Neil Ku ◽  
Carla Walraven ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
High Dose ◽  
Dependent Manner ◽  
Planktonic Cells ◽  
Content Type ◽  
Heparin Sodium ◽  
The Individual

ABSTRACTInfections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin onCandida albicansbiofilms and planktonic cells have not been previously studied. Therefore, we sought to determine thein vitroeffect of a heparin sodium preparation (HP) on biofilms and planktonic cells ofC. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformedC. albicansbiofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P< 0.0001). Pure-H, MP, and PP each inhibitedC. albicansbiofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H havein vitroantifungal activity againstC. albicansmature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention ofC. albicansbiofilms is warranted.

scholarly journals The Novel Arylamidine T-2307 MaintainsIn VitroandIn VivoActivity against Echinocandin-Resistant Candida albicans

2014 ◽  
Vol 59 (2) ◽  
pp. 1341-1343 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Annette W. Fothergill ◽  
Rosie Bocanegra ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Placebo Control ◽  
The Novel ◽  
Content Type ◽  
Fungal Burden ◽  
Potential Use

ABSTRACTWe evaluated thein vitroandin vivoactivities of the investigational arylamidine T-2307 against echinocandin-resistantCandida albicans. T-2307 demonstrated potentin vitroactivity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistantC. albicansinfections.

scholarly journals Antimicrobial Photodynamic Inactivation Inhibits Candida albicans Virulence Factors and ReducesIn VivoPathogenicity

2012 ◽  
Vol 57 (1) ◽  
pp. 445-451 ◽  
Author(s):  
Ilka Tiemy Kato ◽  
Renato Araujo Prates ◽  
Caetano Padial Sabino ◽  
Beth Burgwyn Fuchs ◽  
George P. Tegos ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Virulence Factors ◽  
Sodium Dodecyl ◽  
Systemic Infection ◽  
Tube Formation ◽  
Photodynamic Inactivation ◽  
Content Type ◽  
Daughter Cells

ABSTRACTThe objective of this study was to evaluate whetherCandida albicansexhibits altered pathogenicity characteristics following sublethal antimicrobial photodynamic inactivation (APDI) and if such alterations are maintained in the daughter cells.C. albicanswas exposed to sublethal APDI by using methylene blue (MB) as a photosensitizer (0.05 mM) combined with a GaAlAs diode laser (λ 660 nm, 75 mW/cm2, 9 to 27 J/cm2).In vitro, we evaluated APDI effects onC. albicansgrowth, germ tube formation, sensitivity to oxidative and osmotic stress, cell wall integrity, and fluconazole susceptibility.In vivo, we evaluatedC. albicanspathogenicity with a mouse model of systemic infection. Animal survival was evaluated daily. Sublethal MB-mediated APDI reduced the growth rate and the ability ofC. albicansto form germ tubes compared to untreated cells (P< 0.05). Survival of mice systemically infected withC. albicanspretreated with APDI was significantly increased compared to mice infected with untreated yeast (P< 0.05). APDI increasedC. albicanssensitivity to sodium dodecyl sulfate, caffeine, and hydrogen peroxide. The MIC for fluconazole forC. albicanswas also reduced following sublethal MB-mediated APDI. However, none of those pathogenic parameters was altered in daughter cells ofC. albicanssubmitted to APDI. These data suggest that APDI may inhibit virulence factors and reducein vivopathogenicity ofC. albicans. The absence of alterations in daughter cells indicates that APDI effects are transitory. The MIC reduction for fluconazole following APDI suggests that this antifungal could be combined with APDI to treatC. albicansinfections.

scholarly journals A Salmonella Virulence Factor Activates the NOD1/NOD2 Signaling Pathway

mBio ◽  
2011 ◽  
Vol 2 (6) ◽  
Author(s):  
A. Marijke Keestra ◽  
Maria G. Winter ◽  
Daisy Klein-Douwel ◽  
Mariana N. Xavier ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Type Iii Secretion ◽  
Salmonella Enterica ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Content Type ◽  
Type Iii

ABSTRACTThe invasion-associated type III secretion system (T3SS-1) ofSalmonella entericaserotype Typhimurium (S. Typhimurium) activates the transcription factor NF-κB in tissue culture cells and induces inflammatory responses in animal models through unknown mechanisms. Here we show that bacterial delivery or ectopic expression of SipA, a T3SS-1-translocated protein, led to the activation of the NOD1/NOD2 signaling pathway and consequent RIP2-mediated induction of NF-κB-dependent inflammatory responses. SipA-mediated activation of NOD1/NOD2 signaling was independent of bacterial invasionin vitrobut required an intact T3SS-1. In the mouse colitis model, SipA triggered mucosal inflammation in wild-type mice but not in NOD1/NOD2-deficient mice. These findings implicate SipA-driven activation of the NOD1/NOD2 signaling pathway as a mechanism by which the T3SS-1 induces inflammatory responsesin vitroandin vivo.IMPORTANCESalmonella entericaserotype Typhimurium (S. Typhimurium) deploys a type III secretion system (T3SS-1) to induce intestinal inflammation and benefits from the ensuing host response, which enhances growth of the pathogen in the intestinal lumen. However, the mechanisms by which the T3SS-1 triggers inflammatory responses have not been resolved. Here we show that the T3SS-1 effector protein SipA induces NF-κB activation and intestinal inflammation by activating the NOD1/NOD2 signaling pathway. These data suggest that the T3SS-1 escalates innate responses through a SipA-mediated activation of pattern recognition receptors in the host cell cytosol.

scholarly journals HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

2018 ◽  
Vol 19 (10) ◽  
pp. 3153 ◽  
Author(s):  
J. Muñoz-Bello ◽  
Leslie Olmedo-Nieva ◽  
Leonardo Castro-Muñoz ◽  
Joaquín Manzo-Merino ◽  
Adriana Contreras-Paredes ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Promote Cell Proliferation ◽  
E6 And E7 ◽  
Hpv 18

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

scholarly journals Evaluation of Immunostimulatory Activities of Synthetic Mannose-Containing Structures Mimicking the β-(1→2)-Linked Cell Wall Mannans of Candida albicans

2012 ◽  
Vol 19 (11) ◽  
pp. 1889-1893 ◽  
Author(s):  
Kaarina Ranta ◽  
Kaisa Nieminen ◽  
Filip S. Ekholm ◽  
Moniká Poláková ◽  
Mattias U. Roslund ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Content Type ◽  
Mouse Macrophages ◽  
Ifn Γ ◽  
Low Levels ◽  
Necrosis Factor

ABSTRACTImmunostimulatory properties of synthetic structures mimicking the β-(1→2)-linked mannans ofCandida albicanswere evaluatedin vitro. Contrary to earlier observations, tumor necrosis factor (TNF) production was not detected after stimulation with mannotetraose in mouse macrophages. Divalent disaccharide 1,4-bis(α-d-mannopyranosyloxy)butane induced TNF and some molecules induced low levels of gamma interferon (IFN-γ) in human peripheral blood mononuclear cells (PBMC).

scholarly journals A Network Pharmacology Approach to Predict the Proangiogenesis Mechanism of Huangqi-Honghua Herb Pair after Cerebral Ischemia

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jinyi Cao ◽  
Lu Lei ◽  
Kai Wang ◽  
Jing Sun ◽  
Yi Qiao ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Signaling Pathway ◽  
Target Genes ◽  
Blood Stasis ◽  
Blood Stasis Syndrome ◽  
Network Pharmacology ◽  
Western Blot Assay ◽  
Medicinal Value ◽  
Pharmacological Method

Objective. Huangqi-Honghua herb pair is known for its medicinal value to treat Qi deficiency and blood stasis syndrome with a long history in clinical practice. To understand its possible mechanism in a systematic study, a network pharmacological method was addressed. Methods. Detailed information on the HH compounds was obtained from two public databases, and oral bioavailability (OB) and drug-like (DL) of the compounds were evaluated. A correlation between HH compounds, its potential targets, and known targets was extrapolated, and the herb-compound-target-disease (H-C-T-D) network was established. Next, the pathway enrichment and essential genes were analyzed. Then, three key genes (VEGFA, VEGFR2, and eNOS), highly associated with angiogenesis, were screened and verified through western blot assay. Results. Out of 276 compounds, 21 HH compounds and 78 target genes regulating the major pathways associated with CI in the network are analyzed. The bioactive compounds in HH were active in various signal transduction pathways such as the toll-like receptor signaling pathway, VEGF signaling pathway, TNF signaling pathway, and HIF-1 signaling pathway are important pathways that may regulate anti-inflammatory, antiapoptotic, immune correlation, and antioxidative effects. The core genes are PTGS2, TNF, NOS2, IL6, BCL2, IL1B, SOD2, NOS3, SOD1, MMP9, and VEGFA. The in vitro results suggested that HH treatment could significantly elevate the expression of proangiogenic genes such as VEGFA, VEGFR2, and eNOS compared with OGD groups. Conclusions. Our results predict that HH may regulate the expression of VEGFA, VEGFR2, and eNOS via the VEGF and HIF-1 signaling pathway to promote angiogenesis and alleviate cerebral ischemia injury.

scholarly journals The Quorum-Sensing Molecules Farnesol/Homoserine Lactone and Dodecanol Operate via Distinct Modes of Action in Candida albicans

2011 ◽  
Vol 10 (8) ◽  
pp. 1034-1042 ◽  
Author(s):  
Rebecca A. Hall ◽  
Kara J. Turner ◽  
James Chaloupka ◽  
Fabien Cottier ◽  
Luisa De Sordi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Quorum Sensing ◽  
Signaling Pathway ◽  
Homoserine Lactone ◽  
Burkholderia Cenocepacia ◽  
Camp Signaling ◽  
Mammalian Host ◽  
Content Type ◽  
Hyphal Development ◽  
Natural Flora

ABSTRACTLiving as a commensal,Candida albicansmust adapt and respond to environmental cues generated by the mammalian host and by microbes comprising the natural flora. These signals have opposing effects onC. albicans, with host cues promoting the yeast-to-hyphal transition and bacteria-derived quorum-sensing molecules inhibiting hyphal development. Hyphal development is regulated through modulation of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and it has been postulated that quorum-sensing molecules can affect filamentation by inhibiting the cAMP pathway. Here, we show that both farnesol and 3-oxo-C12-homoserine lactone, a quorum-sensing molecule secreted byPseudomonas aeruginosa, block hyphal development by affecting cAMP signaling; they both directly inhibited the activity of theCandidaadenylyl cyclase, Cyr1p. In contrast, the 12-carbon alcohol dodecanol appeared to modulate hyphal development and the cAMP signaling pathway without directly affecting the activity of Cyr1p. Instead, we show that dodecanol exerted its effects through a mechanism involving theC. albicanshyphal repressor, Sfl1p. Deletion ofSFL1did not affect the response to farnesol but did interfere with the response to dodecanol. Therefore, quorum sensing inC. albicansis mediated via multiple mechanisms of action. Interestingly, our experiments raise the possibility that theBurkholderia cenocepaciadiffusible signal factor, BDSF, also mediates its effects via Sfl1p, suggesting that dodecanol's mode of action, but not farnesol or 3-oxo-C12-homoserine lactone, may be used by other quorum-sensing molecules.

scholarly journals Melanin Externalization in Candida albicans Depends on Cell Wall Chitin Structures

2010 ◽  
Vol 9 (9) ◽  
pp. 1329-1342 ◽  
Author(s):  
Claire A. Walker ◽  
Beatriz L. Gómez ◽  
Héctor M. Mora-Montes ◽  
Kevin S. Mackenzie ◽  
Carol A. Munro ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Cell Walls ◽  
Chitin Synthesis ◽  
Melanin Production ◽  
Content Type ◽  
Encoding Gene ◽  
Chitinase Genes

ABSTRACT The fungal pathogen Candida albicans produces dark-pigmented melanin after 3 to 4 days of incubation in medium containing l-3,4-dihydroxyphenylalanine (l-DOPA) as a substrate. Expression profiling of C. albicans revealed very few genes significantly up- or downregulated by growth in l-DOPA. We were unable to determine a possible role for melanin in the virulence of C. albicans. However, we showed that melanin was externalized from the fungal cells in the form of electron-dense melanosomes that were free or often loosely bound to the cell wall exterior. Melanin production was boosted by the addition of N-acetylglucosamine to the medium, indicating a possible association between melanin production and chitin synthesis. Melanin externalization was blocked in a mutant specifically disrupted in the chitin synthase-encoding gene CHS2. Melanosomes remained within the outermost cell wall layers in chs3Δ and chs2Δ chs3Δ mutants but were fully externalized in chs8Δ and chs2Δ chs8Δ mutants. All the CHS mutants synthesized dark pigment at equivalent rates from mixed membrane fractions in vitro, suggesting it was the form of chitin structure produced by the enzymes, not the enzymes themselves, that was involved in the melanin externalization process. Mutants with single and double disruptions of the chitinase genes CHT2 and CHT3 and the chitin pathway regulator ECM33 also showed impaired melanin externalization. We hypothesize that the chitin product of Chs3 forms a scaffold essential for normal externalization of melanosomes, while the Chs8 chitin product, probably produced in cell walls in greater quantity in the absence of CHS2, impedes externalization.

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