scholarly journals An Internal Polarity Landmark Is Important for Externally Induced Hyphal Behaviors in Candida albicans

2008 ◽  
Vol 7 (4) ◽  
pp. 712-720 ◽  
Author(s):  
Alexandra Brand ◽  
Anjalee Vacharaksa ◽  
Catherine Bendel ◽  
Jennifer Norton ◽  
Paula Haynes ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Kidney Tissue ◽  
Systemic Infection ◽  
Cell Cortex ◽  
Environmental Cues ◽  
Growth Responses ◽  
Directional Growth ◽  
Internal Polarity ◽  
Hyphal Tip

ABSTRACT Directional growth is a function of polarized cells such as neurites, pollen tubes, and fungal hyphae. Correct orientation of the extending cell tip depends on signaling pathways and effectors that mediate asymmetric responses to specific environmental cues. In the hyphal form of the eukaryotic fungal pathogen Candida albicans, these responses include thigmotropism and galvanotropism (hyphal turning in response to changes in substrate topography and imposed electrical fields, respectively) and penetration into semisolid substrates. During vegetative growth in C. albicans, as in the model yeast Saccharomyces cerevisiae, the Ras-like GTPase Rsr1 mediates internal cellular cues to position new buds in a prespecified pattern on the mother cell cortex. Here, we demonstrate that Rsr1 is also important for hyphal tip orientation in response to the external environmental cues that induce thigmotropic and galvanotropic growth. In addition, Rsr1 is involved in hyphal interactions with epithelial cells in vitro and its deletion diminishes the hyphal invasion of kidney tissue during systemic infection. Thus, Rsr1, an internal polarity landmark in yeast, is also involved in polarized growth responses to asymmetric environmental signals, a paradigm that is different from that described for the homologous protein in S. cerevisiae. Rsr1 may thereby contribute to the pathogenesis of C. albicans infections by influencing hyphal tip responses triggered by interaction with host tissues.

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 Deletion of the ATP2 Gene in Candida albicans Blocks Its Escape From Macrophage Clearance

2021 ◽  
Vol 11 ◽  
Author(s):  
Yishan Zhang ◽  
Chuanyan Tang ◽  
Zhanpeng Zhang ◽  
Shuixiu Li ◽  
Yajing Zhao ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Drug Target ◽  
Fungal Infections ◽  
Carbon Sources ◽  
Systemic Infection ◽  
Invasive Infection ◽  
First Line ◽  
Dramatic Decrease

Macrophages provide the first-line defense against invasive fungal infections and, therefore, escape from macrophage becomes the basis for the establishment of Candida albicans invasive infection. Here, we found that deletion of ATP2 (atp2Δ/Δ) in C. albicans resulted in a dramatic decrease from 69.2% (WT) to 1.2% in the escape rate in vitro. The effect of ATP2 on macrophage clearance stands out among the genes currently known to affect clearance. In the normal mice, the atp2Δ/Δ cells were undetectable in major organs 72 h after systemic infection, while WT cells persisted in vivo. However, in the macrophage-depleted mice, atp2Δ/Δ could persist for 72 h at an amount comparable to that at 24 h. Regarding the mechanism, WT cells sustained growth and switched to hyphal form, which was more conducive to escape from macrophages, in media that mimic the glucose-deficient environment in macrophages. In contrast, atp2Δ/Δ cells can remained viable but were unable to complete morphogenesis in these media, resulting in them being trapped within macrophages in the yeast form. Meanwhile, atp2Δ/Δ cells were killed by oxidative stress in alternative carbon sources by 2- to 3-fold more than WT cells. Taken together, ATP2 deletion prevents C. albicans from escaping macrophage clearance, and therefore ATP2 has a functional basis as a drug target that interferes with macrophage clearance.

scholarly journals Adhesion of Candida albicans to Endothelial Cells under Physiological Conditions of Flow

2009 ◽  
Vol 77 (9) ◽  
pp. 3872-3878 ◽  
Author(s):  
Sarah E. W. Grubb ◽  
Craig Murdoch ◽  
Peter E. Sudbery ◽  
Stephen P. Saville ◽  
Jose L. Lopez-Ribot ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Candida Albicans ◽  
Blood Vessels ◽  
Systemic Infection ◽  
Multiple Organ ◽  
Adhesion Assay ◽  
Conflicting Evidence

ABSTRACT Candida albicans is a commensal organism that under certain circumstances can become pathogenic. During systemic infection C. albicans is disseminated via the circulation to distant organs, where it causes multiple organ failure. Despite the severity of systemic C. albicans infection, little is known about the mechanisms involved in the adhesion of this organism to the endothelium lining blood vessels. Previous studies have used static assays to examine adhesion. However, these do not realistically model blood vessels, where circulating C. albicans cells must adhere to the endothelium under conditions of flow and shear stress. Furthermore, there is conflicting evidence concerning the role played by yeast, pseudohyphal, and hyphal forms of C. albicans in adhesion to endothelium. To test the hypothesis that there may be differences in the abilities of these three morphogenic forms of C. albicans to adhere to endothelium under conditions of flow, we developed an in vitro flow adhesion assay. We found that all three forms of C. albicans rapidly bound to confluent endothelial cells under conditions of flow. Maximum adhesion was found at low shear stress levels similar to that found in postcapillary venules. Moreover, yeast forms bound in significantly greater numbers than did pseudohyphal and hyphal forms, respectively, contrasting with previous findings from static assays. These findings are consistent with recent in vivo data suggesting that yeast forms may be capable of adhering to the endothelium and migrating into the tissues before undergoing morphogenic change to cause tissue damage.

scholarly journals High Resistance to Oxidative Stress in the Fungal Pathogen Candida glabrata Is Mediated by a Single Catalase, Cta1p, and Is Controlled by the Transcription Factors Yap1p, Skn7p, Msn2p, and Msn4p

2008 ◽  
Vol 7 (5) ◽  
pp. 814-825 ◽  
Author(s):  
Mayra Cuéllar-Cruz ◽  
Marcela Briones-Martin-del-Campo ◽  
Israel Cañas-Villamar ◽  
Javier Montalvo-Arredondo ◽  
Lina Riego-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Adaptive Response ◽  
Fungal Pathogen ◽  
Candida Glabrata ◽  
Systemic Infection ◽  
Oxidative Stress Response

ABSTRACT We characterized the oxidative stress response of Candida glabrata to better understand the virulence of this fungal pathogen. C. glabrata could withstand higher concentrations of H2O2 than Saccharomyces cerevisiae and even Candida albicans. Stationary-phase cells were extremely resistant to oxidative stress, and this resistance was dependent on the concerted roles of stress-related transcription factors Yap1p, Skn7p, and Msn4p. We showed that growing cells of C. glabrata were able to adapt to high levels of H2O2 and that this adaptive response was dependent on Yap1p and Skn7p and partially on the general stress transcription factors Msn2p and Msn4p. C. glabrata has a single catalase gene, CTA1, which was absolutely required for resistance to H2O2 in vitro. However, in a mouse model of systemic infection, a strain lacking CTA1 showed no effect on virulence.

scholarly journals Candida albicans Septin Mutants Are Defective for Invasive Growth and Virulence

2003 ◽  
Vol 71 (7) ◽  
pp. 4045-4051 ◽  
Author(s):  
Amy J. Warenda ◽  
Sarah Kauffman ◽  
Taylor P. Sherrill ◽  
Jeffrey M. Becker ◽  
James B. Konopka
Keyword(s):  
Candida Albicans ◽  
Systemic Infection ◽  
Hyphal Growth ◽  
Invasive Growth ◽  
Important Virulence Factor ◽  
Opportunistic Human Pathogen ◽  
Cytoskeletal Elements ◽  
Organ Invasion

ABSTRACT Hyphal growth of Candida albicans is implicated as an important virulence factor for this opportunistic human pathogen. Septin proteins, a family of cytoskeletal elements that regulate membrane events and are important for proper morphogenesis of C. albicans, were examined for their role in tissue invasion and virulence in the mouse model of systemic infection. In vitro, septin mutants are only mildly defective for hyphal growth in liquid culture but display pronounced defects for invasive growth into agar. In vivo, the septin mutants were found to exhibit attenuated virulence. However, mice infected with the mutants displayed high fungal burdens in their kidneys without obvious symptoms of disease. Histological examination of infected kidneys revealed defects in organ invasion for the cdc10Δ and cdc11Δ deletion mutants, which displayed both reduced tissue penetration and noninvasive fungal masses. Thus, the septin proteins are necessary for invasive growth, which appears to be more important to the successful pathogenesis of C. albicans than hyphal growth alone.

scholarly journals Hypoxic Adaptation by Efg1 Regulates Biofilm Formation by Candida albicans

2009 ◽  
Vol 75 (11) ◽  
pp. 3663-3672 ◽  
Author(s):  
Catrin Stichternoth ◽  
Joachim F. Ernst
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Transcriptional Control ◽  
Sulfur Metabolism ◽  
Systemic Infection ◽  
Inducible Promoter ◽  
Biofilm Growth ◽  
Hypoxic Adaptation ◽  
Biofilm Development

ABSTRACT Hypoxia is encountered frequently by Candida albicans during systemic infection of the human host. We tested if hypoxia allows biofilm formation by C. albicans, which is a major cause of perseverance and antifungal resistance in C. albicans infections. Using an in vitro biofilm system, we unexpectedly discovered that several positive regulators of biofilm formation during normoxia, including Tec1, Ace2, Czf1, Och1, and Als3, had little or no influence on biofilm development during hypoxia, irrespective of the carbon dioxide level, indicating that C. albicans biofilm pathways differ depending on the oxygen level. In contrast, the Efg1 and Flo8 regulators were required for both normoxic and hypoxic biofilm formation. To explore the role of Efg1 during hypoxic and/or biofilm growth, we determined transcriptome kinetics following release of EFG1 expression by a system under transcriptional control of a doxycycline-inducible promoter. During hypoxia, Efg1 rapidly induced expression of all major classes of genes known to be associated with normoxic biofilm formation, including genes involved in glycolysis, sulfur metabolism, and antioxidative and peroxisome activities, as well as genes for iron uptake. The results suggest that hypoxic adaptation mediated by the Efg1 and Flo8 regulators is required even during normoxic biofilm development, while hypoxic biofilm formation in deep tissues or in organs may generate foci of C. albicans infections.

scholarly journals Candida albicans PPG1, a serine/threonine phosphatase, plays a vital role in central carbon metabolisms under filament-inducing conditions: A multi-omics approach

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0259588
Author(s):  
Mohammad Tahseen A. L. Bataineh ◽  
Nelson Cruz Soares ◽  
Mohammad Harb Semreen ◽  
Stefano Cacciatore ◽  
Nihar Ranjan Dash ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Vital Role ◽  
Environmental Cues ◽  
Sequencing Analysis ◽  
Wild Type ◽  
Tissue Invasion ◽  
Central Carbon ◽  
Life Threatening ◽  
Upregulated Genes

Candida albicans is the leading cause of life-threatening bloodstream candidiasis, especially among immunocompromised patients. The reversible morphological transition from yeast to hyphal filaments in response to host environmental cues facilitates C. albicans tissue invasion, immune evasion, and dissemination. Hence, it is widely considered that filamentation represents one of the major virulence properties in C. albicans. We have previously characterized Ppg1, a PP2A-type protein phosphatase that controls filament extension and virulence in C. albicans. This study conducted RNA sequencing analysis of samples obtained from C. albicans wild type and ppg1Δ/Δ strains grown under filament-inducing conditions. Overall, ppg1Δ/Δ strain showed 1448 upregulated and 710 downregulated genes, representing approximately one-third of the entire annotated C. albicans genome. Transcriptomic analysis identified significant downregulation of well-characterized genes linked to filamentation and virulence, such as ALS3, HWP1, ECE1, and RBT1. Expression analysis showed that essential genes involved in C. albicans central carbon metabolisms, including GDH3, GPD1, GPD2, RHR2, INO1, AAH1, and MET14 were among the top upregulated genes. Subsequent metabolomics analysis of C. albicans ppg1Δ/Δ strain revealed a negative enrichment of metabolites with carboxylic acid substituents and a positive enrichment of metabolites with pyranose substituents. Altogether, Ppg1 in vitro analysis revealed a link between metabolites substituents and filament formation controlled by a phosphatase to regulate morphogenesis and virulence.

scholarly journals Staphylococcus aureus Synergized with Candida albicans to Increase the Pathogenesis and Drug Resistance in Cutaneous Abscess and Peritonitis Murine Models

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1036
Author(s):  
Yao Hu ◽  
Yulong Niu ◽  
Xingchen Ye ◽  
Chengguang Zhu ◽  
Ting Tong ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Resistance ◽  
Candida Albicans ◽  
Synergistic Effects ◽  
Systemic Infection ◽  
Microbial Interactions ◽  
Murine Models ◽  
Resistant Genes ◽  
Antibacterial And Antifungal

The mixed species of Staphylococcus aureus and Candida albicans can cause infections on skin, mucosa or bloodstream; however, mechanisms of their cross-kingdom interactions related to pathogenesis and drug resistance are still not clear. Here an increase of S. aureus proliferation and biofilm formation was observed in S. aureus and C. albicans dual-species culture, and the synergistic pathogenic effect was then confirmed in both local (cutaneous abscess) and systemic infection (peritonitis) murine models. According to the transcriptome analysis of the dual-species culture, virulence factors of S. aureus were significantly upregulated. Surprisingly, the beta-lactams and vancomycin-resistant genes in S. aureus as well as azole-resistant genes in C. albicans were also significantly increased. The synergistic effects on drug resistance to both antibacterial and antifungal agents were further proved both in vitro and in cutaneous abscess and peritonitis murine models treated by methicillin, vancomycin and fluconazole. The synergistic interactions between S. aureus and C. albicans on pathogenesis and drug resistance highlight the importance of targeting the microbial interactions in polyspecies-associated infections.

scholarly journals The pH of the Host Niche Controls Gene Expression in and Virulence of Candida albicans

1998 ◽  
Vol 66 (7) ◽  
pp. 3317-3325 ◽  
Author(s):  
Flavia De Bernardis ◽  
Fritz A. Mühlschlegel ◽  
Antonio Cassone ◽  
William A. Fonzi
Keyword(s):  
Candida Albicans ◽  
Gene Dosage ◽  
Systemic Infection ◽  
Infection Model ◽  
Null Mutant ◽  
Vaginal Infection ◽  
Pathogenic Potential ◽  
Hyphal Development ◽  
Virulence Phenotype

ABSTRACT Little is known of the biological attributes conferring pathogenicity on the opportunistic fungal pathogen Candida albicans. Infection by this pathogen, as for bacterial pathogens, may rely upon environmental signals within the host niche to regulate the expression of virulence determinants. To determine if C. albicans responds to the pH of the host niche, we tested the virulence of strains with mutations in either of two pH-regulated genes, PHR1 and PHR2. In vitro,PHR1 is expressed when the ambient pH is at 5.5 or higher and deletion of the gene results in growth and morphological defects at neutral to alkaline pHs. Conversely, PHR2 is expressed at an ambient pH below 5.5, and the growth and morphology of the null mutant is compromised below this pH. A PHR1 null mutant was avirulent in a mouse model of systemic infection but uncompromised in its ability to cause vaginal infection in rats. Since systemic pH is near neutrality and vaginal pH is around 4.5, the virulence phenotype paralleled the pH dependence of the in vitro phenotypes. The virulence phenotype of a PHR2 null mutant was the inverse. The mutant was virulent in a systemic-infection model but avirulent in a vaginal-infection model. Heterozygous mutants exhibited partial reductions in their pathogenic potential, suggesting a gene dosage effect. Unexpectedly, deletion of PHR2 did not prevent hyphal development in vaginal tissue, suggesting that it is not essential for hyphal development in this host niche. The results suggest that the pH of the infection site regulates the expression of genes essential to survival within that niche. This implies that the study of environmentally regulated genes may provide a rationale for understanding the pathobiology of C. albicans.

scholarly journals Trans-cellular tunnels induced by the fungal pathogen Candida albicans facilitate invasion through successive epithelial cells without host damage

2021 ◽  
Author(s):  
Joy Lachat ◽  
Alice Pascault ◽  
Delphine Thibaut ◽  
Rémi Le Borgne ◽  
Jean-Marc Verbavatz ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Single Cell Analysis ◽  
Three Dimensional ◽  
Systemic Infection ◽  
Host Cells ◽  
Galectin 3 ◽  
Opportunistic Fungal Pathogen ◽  
Epithelial Layers

SummaryThe opportunistic fungal pathogen Candida albicans is normally commensal, residing in the mucosa of most healthy individuals. In susceptible hosts, its filamentous hyphal form can invade epithelial layers leading to superficial or severe systemic infection. Invasion is mainly intracellular, though it causes no apparent damage to host cells. We investigated the invasive lifestyle of C. albicans in vitro using live-cell imaging and the damage-sensitive reporter galectin-3. Quantitative single cell analysis showed that invasion can result in host membrane breaching at different stages of invasion and cell death, or in traversal of host cells without membrane breaching. Membrane labelling and three-dimensional “volume” electron microscopy revealed that hyphae can traverse several host cells within trans-cellular tunnels that are progressively remodelled and may undergo ‘inflations’ linked to host glycogen stores, possibly during nutrient uptake. Thus, C. albicans invade epithelial tissues by either inflicting or avoiding host damage, the latter facilitated by trans-cellular tunnelling.

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