scholarly journals Hgc1 Mediates Dynamic Candida albicans-Endothelium Adhesion Events during Circulation

2009 ◽  
Vol 9 (2) ◽  
pp. 278-287 ◽  
Author(s):  
Duncan Wilson ◽  
Bernhard Hube
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Candida Albicans ◽  
Pathogenic Fungus ◽  
Interaction Model ◽  
Serum Factors ◽  
Content Type ◽  
Disseminated Candidiasis ◽  
Human Pathogenic Fungus

ABSTRACT Common iatrogenic procedures can result in translocation of the human pathogenic fungus Candida albicans from mucosal surfaces to the bloodstream. Subsequent disseminated candidiasis and infection of deep-seated organs may occur if the fungus is not eliminated by blood cells. In these cases, fungal cells adhere to the endothelial cells of blood vessels, penetrate through endothelial layers, and invade deeper tissue. In this scenario, endothelial adhesion events must occur during circulation under conditions of physiological blood pressure. To investigate the fungal and host factors which contribute to this essential step of disseminated candidiasis, we have developed an in vitro circulatory C. albicans-endothelium interaction model. We demonstrate that both C. albicans yeast and hyphae can adhere under flow at a pressure similar to capillary blood pressure. Serum factors significantly enhanced the adhesion potential of viable but not killed C. albicans cells to endothelial cells. During circulation, C. albicans cells produced hyphae and the adhesion potential first increased, then decreased with time. We provide evidence that a specific temporal event in the yeast-to-hyphal transition, regulated by the G1 cyclin Hgc1, is critical for C. albicans-endothelium adhesion during circulation.

scholarly journals Human Endothelial Cells Internalize Candida parapsilosis via N-WASP-Mediated Endocytosis

2013 ◽  
Vol 81 (8) ◽  
pp. 2777-2787 ◽  
Author(s):  
Tatsushi Shintaku ◽  
Kyle A. Glass ◽  
Matthew P. Hirakawa ◽  
Sarah J. Longley ◽  
Richard J. Bennett ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Candida Parapsilosis ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Human Endothelial Cells ◽  
Serum Factors ◽  
Content Type ◽  
Disseminated Candidiasis ◽  
Interfering Rna

ABSTRACTCandida parapsilosisis a frequent cause of disseminated candidiasis and is associated with significant morbidity and mortality. Although important in pathogenesis, interactions of this organism with endothelial cells have received less attention than those ofCandida albicans. Internalization ofC. parapsilosisby monolayers of human endothelial cells was examined in anin vitroassay and compared to that ofC. albicans. Both live and heat-killed yeast were efficiently internalized, with heat-killed yeast subsequently being detected in an acidic subcompartment. Internalization was marked by a process of engulfment by thin membrane extensions from the endothelium. Efficiency of internalization differed among different clinical isolates and species of yeast. Opsonization ofC. parapsilosisby serum factors was not sufficient to cause endocytosis; instead, serum appeared to directly stimulate endothelial uptake. Colocalization of endothelial actin and N-WASP at sites ofC. parapsilosisinternalization was observed. A Förster-resonance energy transfer (FRET) probe for N-WASP activity showed active N-WASP at sites of internalization for both live and heat-killedC. parapsilosisandC. albicans. An actin nucleation inhibitor (cytochalasin D) and an N-WASP inhibitor (wiskostatin) both inhibited uptake of heat-killedC. parapsilosis, as did short interfering RNA-mediated ablation of N-WASP. Thus, endocytosis by endothelial cells may represent a means of traversal of the blood vessel wall by yeast during disseminated candidiasis, and N-WASP may play a key role in the process.

scholarly journals SR-Like RNA-Binding Protein Slr1 Affects Candida albicans Filamentation and Virulence

2013 ◽  
Vol 81 (4) ◽  
pp. 1267-1276 ◽  
Author(s):  
Chaiyaboot Ariyachet ◽  
Norma V. Solis ◽  
Yaoping Liu ◽  
Nemani V. Prasadarao ◽  
Scott G. Filler ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Candida Albicans ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Umbilical Vein ◽  
Polarized Growth ◽  
Content Type ◽  
Fungal Burden

ABSTRACTCandida albicanscauses both mucosal and disseminated infections, and its capacity to grow as both yeast and hyphae is a key virulence factor. Hyphal formation is a type of polarized growth, and members of the SR (serine-arginine) family of RNA-binding proteins influence polarized growth of bothSaccharomyces cerevisiaeandAspergillus nidulans. Therefore, we investigated whether SR-like proteins affect filamentous growth and virulence ofC. albicans. BLAST searches withS. cerevisiaeSR-like protein Npl3 (ScNpl3) identified twoC. albicansproteins: CaNpl3, an apparent ScNpl3 ortholog, and Slr1, anotherSR-likeRNA-binding protein with no closeS. cerevisiaeortholog. Whereas ScNpl3 was critical for growth, deletion ofNPL3inC. albicansresulted in few phenotypic changes. In contrast, theslr1Δ/Δ mutant had a reduced growth ratein vitro, decreased filamentation, and impaired capacity to damage epithelial and endothelial cellsin vitro. Mice infected intravenously with theslr1Δ/Δ mutant strain had significantly prolonged survival compared to that of mice infected with the wild-type orslr1Δ/Δ mutant complemented withSLR1(slr1Δ/Δ+SLR1) strain, without a concomitant decrease in kidney fungal burden. Histopathology, however, revealed differential localization ofslr1Δ/Δ hyphal and yeast morphologies within the kidney. Mice infected withslr1Δ/Δ cells also had an increased brain fungal burden, which correlated with increased invasion of brain, but not umbilical vein, endothelial cellsin vitro. The enhanced brain endothelial cell invasion was likely due to the increased surface exposure of the Als3 adhesin onslr1Δ/Δ cells. Our results indicate that Slr1 is an SR-like protein that influencesC. albicansgrowth, filamentation, host cell interactions, and virulence.

scholarly journals Diverse Nitrogen Sources in Seminal Fluid Act in Synergy To Induce Filamentous Growth of Candida albicans

2015 ◽  
Vol 81 (8) ◽  
pp. 2770-2780 ◽  
Author(s):  
Francisco J. Alvarez ◽  
Kicki Ryman ◽  
Cornelis Hooijmaijers ◽  
Vincent Bulone ◽  
Per O. Ljungdahl
Keyword(s):  
Candida Albicans ◽  
Seminal Fluid ◽  
Pathogenic Fungus ◽  
Nitrogen Sources ◽  
Filamentous Growth ◽  
Vaginal Fluid ◽  
Content Type ◽  
Intermittent Contact ◽  
Induced Changes

ABSTRACTThe pathogenic fungusCandida albicansis the leading cause of vulvovaginal candidiasis (VVC). VVC represents a major quality-of-life issue for women during their reproductive years, a stage of life where the vaginal epithelium is subject to periodic hormonally induced changes associated with menstruation and concomitant exposure to serum as well as potential intermittent contact with seminal fluid. Seminal fluid potently triggersCandida albicansto switch from yeastlike to filamentous modes of growth, a developmental response tightly linked to virulence. Conversely, vaginal fluid inhibits filamentation. Here, we used artificial formulations of seminal and vaginal fluids that faithfully mimic genuine fluids to assess the contribution of individual components within these fluids to filamentation. The high levels of albumin, amino acids, andN-acetylglucosamine in seminal fluid act synergistically as potent inducers of filamentous growth, even at atmospheric levels of CO2and reduced temperatures (30°C). Using a simplifiedin vitromodel that mimics the natural introduction of seminal fluid into the vulvovaginal environment, a pulse of artificial seminal fluid (ASF) was found to exert an enduring potential to overcome the inhibitory efficacy of artificial vaginal fluid (AVF) on filamentation. These findings suggest that a transient but substantial change in the nutrient levels within the vulvovaginal environment during unprotected coitus can induce residentC. albicanscells to engage developmental programs associated with virulent growth.

scholarly journals Global Transcriptomic Analysis of the Candida albicans Response to Treatment with a Novel Inhibitor of Filamentation

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Jesus A. Romo ◽  
Hao Zhang ◽  
Hong Cai ◽  
David Kadosh ◽  
Julia R. Koehler ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Small Molecule ◽  
Pathogenic Fungus ◽  
Transcriptional Profiling ◽  
Response To Treatment ◽  
Sequencing Analysis ◽  
Transport Pathways ◽  
Content Type

ABSTRACT The opportunistic pathogenic fungus Candida albicans can cause devastating infections in immunocompromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and damage tissues, and the expression of genes associated with a number of pathogenetic mechanisms is also coordinately regulated with the yeast-to-hypha conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans. We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small-molecule inhibitors of C. albicans filamentation and characterized its activity both in vitro and in vivo. This compound appears to be a promising candidate for the development of alternative antivirulence strategies for the treatment of C. albicans infections. In this study, we performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall, treatment with compound 9029936 resulted in 618 upregulated and 702 downregulated genes. Not surprisingly, some of the most downregulated genes included well-characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an overrepresentation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among the genes downregulated during treatment with this leading compound. Interestingly, the top upregulated genes suggested an enhancement of vesicular transport pathways, particularly those involving SNARE interactions. IMPORTANCE These results from whole-genome transcriptional profiling provide further insights into the biological activity and mode of action of a small-molecule inhibitor of C. albicans filamentation. This information will assist in the development of novel antivirulence strategies against C. albicans infections.

scholarly journals In VitroActivity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions andIn VivoEfficacy in a Murine Model of Oral Candidiasis

2015 ◽  
Vol 59 (12) ◽  
pp. 7611-7620 ◽  
Author(s):  
Taissa Vieira Machado Vila ◽  
Ashok K. Chaturvedi ◽  
Sonia Rozental ◽  
Jose L. Lopez-Ribot
Keyword(s):  
Candida Albicans ◽  
Murine Model ◽  
Biofilm Formation ◽  
Pathogenic Fungus ◽  
Oral Candidiasis ◽  
Antifungal Drugs ◽  
Drug Candidate ◽  
Content Type

ABSTRACTThe generation of a new antifungal againstCandida albicansbiofilms has become a major priority, since biofilm formation by this opportunistic pathogenic fungus is usually associated with an increased resistance to azole antifungal drugs and treatment failures. Miltefosine is an alkyl phospholipid with promising antifungal activity. Here, we report that, when tested under planktonic conditions, miltefosine displays potentin vitroactivity against multiple fluconazole-susceptible and -resistantC. albicansclinical isolates, including isolates overexpressing efflux pumps and/or with well-characterized Erg11 mutations. Moreover, miltefosine inhibitsC. albicans biofilm formation and displays activity against preformed biofilms. Serial passage experiments confirmed that miltefosine has a reduced potential to elicit resistance, and screening of a library ofC. albicanstranscription factor mutants provided additional insight into the activity of miltefosine againstC. albicansgrowing under planktonic and biofilm conditions. Finally, we demonstrate thein vivoefficacy of topical treatment with miltefosine in the murine model of oropharyngeal candidiasis. Overall, our results confirm the potential of miltefosine as a promising antifungal drug candidate, in particular for the treatment of azole-resistant and biofilm-associated superficial candidiasis.

scholarly journals Investigation of the Function of Candida albicans Als3 by Heterologous Expression in Candida glabrata

2013 ◽  
Vol 81 (7) ◽  
pp. 2528-2535 ◽  
Author(s):  
Yue Fu ◽  
Quynh T. Phan ◽  
Guanpingsheng Luo ◽  
Norma V. Solis ◽  
Yaoping Liu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Candida Albicans ◽  
Candida Glabrata ◽  
Content Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Disseminated Infection ◽  
Cell Lining ◽  
The Brain

ABSTRACTDuring hematogenously disseminated infection, blood-borneCandida albicansinvades the endothelial cell lining of the vasculature to invade the deep tissues. Although theC. albicansAls3 invasin is critical for invasion and damage of endothelial cellsin vitro, aC. albicans als3Δ/Δ mutant has normal virulence in the mouse model of disseminated infection. We hypothesized that the contribution of Als3 to virulence is obscured by the presence of additionalC. albicansinvasins. To elucidate thein vivofunction of Als3, we heterologously expressedC. albicans ALS3inCandida glabrata, a yeast that lacks a closeALS3ortholog and has low virulence in mice. We found that following intravenous inoculation into mice, theALS3-expressing strain preferentially trafficked to the brain, where it induced significantly elevated levels of myeloperoxidase, tumor necrosis factor, monocyte chemoattractant protein 1, and gamma interferon. Also, theALS3-expressing strain had enhanced adherence to and invasion of human brain microvascular endothelial cellsin vitro, demonstrating a potential mechanism forALS3-mediated neurotropism. In addition, upon initiation of infection, theALS3-expressing strain had increased trafficking to the cortex of the kidneys. With prolonged infection, this strain persisted in the kidneys at significantly higher levels than the control strain but did not induce an elevated inflammatory response. Finally, theALS3-expressing strain had increased resistance to neutrophil killingin vitro. These results indicate that during disseminated infection, Als3 mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys.

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.

Sign in / Sign up

Export Citation Format

Share Document