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.

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 Virulence of the Fungal Pathogen Candida albicans Requires the Five Isoforms of Protein Mannosyltransferases

2005 ◽  
Vol 73 (8) ◽  
pp. 4571-4580 ◽  
Author(s):  
Mahmoud Rouabhia ◽  
Martin Schaller ◽  
Cristina Corbucci ◽  
Anna Vecchiarelli ◽  
Stephan K.-H. Prill ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Fungal Pathogen ◽  
Antifungal Agents ◽  
Three Dimensional ◽  
Secretory Proteins ◽  
In Vitro Growth ◽  
Specific Host ◽  
Three Dimensional Models

ABSTRACT The PMT gene family in Candida albicans encodes five isoforms of protein mannosyltransferases (Pmt proteins Pmt1p, Pmt2p, Pmt4p, Pmt5p, and Pmt6p) that initiate O mannosylation of secretory proteins. We compared virulence characteristics of pmt mutants in two complex, three-dimensional models of localized candidiasis, using reconstituted human epithelium (RHE) and engineered human oral mucosa (EHOM); in addition, mutants were tested in a mouse model of hematogenously disseminated candidiasis (HDC). All pmt mutants showed attenuated virulence in the HDC model and at least one model of localized candidiasis. The pmt5 mutant, which lacks in vitro growth phenotypes, was less virulent in the EHOM and HDC assays but had no consistent phenotype in the RHE assay. In contrast, the pmt4 and pmt6 mutants were less virulent in the RHE and HDC assays but not in the EHOM assay. The results stress the contribution of all Pmt isoforms to the virulence of C. albicans and suggest that the importance of individual Pmt isoforms may differ in specific host niches. We propose that Pmt proteins may be suitable targets for future novel classes of antifungal agents.

scholarly journals Human gut bifidobacteria inhibit the growth of the opportunistic fungal pathogen Candida albicans

2021 ◽  
Author(s):  
Liviana Ricci ◽  
Joanna Mackie ◽  
Gillian E Donachie ◽  
Ambre Chapuis ◽  
Kristyna Mezerova ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Inhibitory Activity ◽  
Fungal Pathogen ◽  
Antagonistic Activity ◽  
Rrna Gene ◽  
Human Gut ◽  
Bifidobacterium Adolescentis ◽  
Opportunistic Fungal Pathogen

The human gut microbiota protects the host from invading pathogens and the overgrowth of indigenous opportunistic species via mechanisms such as competition for nutrients and by production of antimicrobial compounds. Here, we investigated the antagonist activity of human gut bacteria towards Candida albicans, an opportunistic fungal pathogen that can cause severe infections and mortality in susceptible patients. Co-culture batch incubations of C. albicans in the presence of faecal microbiota from six different healthy individuals revealed varying levels of inhibitory activity against C. albicans. 16S rRNA gene sequence profiling of these faecal co-culture bacterial communities showed that the Bifidobacteriaceae family, and Bifidobacterium adolescentis in particular, were most correlated with antagonistic activity against C. albicans. Follow up mechanistic studies confirmed that culture supernatants of Bifidobacterium species, particularly B. adolescentis, inhibited C. albicans in vitro under both aerobic and anaerobic conditions. Production of the fermentation acids acetate and lactate, together with the concomitant decrease in pH, were strong drivers of the inhibitory activity. Bifidobacteria may therefore represent attractive targets for the development of probiotics and prebiotic interventions tailored to enhance inhibitory activity against C. albicans in vivo.

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 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 Bifidobacterium adolescentis shows potential to strengthen host defence against gastrointestinal infection via inhibition of the opportunistic pathogen Candida albicans and stimulation of human-isolated macrophages killing capacity in vitro

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Liviana Ricci ◽  
Joanna Mackie ◽  
Megan D. Lenardon ◽  
Caitlin Jukes ◽  
Ahmed N. Hegazy ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Bacterial Species ◽  
Opportunistic Pathogen ◽  
Limited Information ◽  
Human Gut ◽  
Bifidobacterium Adolescentis ◽  
Host Immune Responses ◽  
Opportunistic Fungal Pathogen ◽  
Antimicrobial Metabolites

The human gut microbiota enhances the host’s resistance to enteric pathogens via colonisation resistance, a phenomenon that is driven by multiple mechanisms, such as production of antimicrobial metabolites and activation of host immune responses. However, there is limited information on how individual gut bacterial species, particularly many of the dominant anaerobes, might impact the host’s defence. This study investigated the potential of specific human gut isolates to bolster the host’s resistance to infection. First, by antagonising the opportunistic fungal pathogen Candida albicans, and secondly, by modulating the killing capacity of human-isolated macrophages in vitro. Co-culturing C. albicans with faecal microbiota from different healthy individuals revealed varying levels of fungal inhibition. In vitro assays with a panel of representative human gut anaerobes confirmed that culture supernatants from certain bacterial isolates, in particular of Bifidobacterium adolescentis, significantly inhibited C. albicans growth. Mechanistic studies revealed that microbial fermentation acids including acetate and lactate, in combination with the associated decrease in pH, were strong drivers of this inhibitory activity. In the second in vitro assay, human-isolated macrophages were exposed to bacterial supernatants, and subsequently tested for their capacity to eliminate adherent-invasive Escherichia coli. Among the gut anaerobes tested, B. adolescentis was revealed to exert the strongest immunostimulatory and killing effect when compared to the unstimulated macrophages control. B. adolescentis is known to be stimulated by dietary consumption of resistant starch andmay therefore represent an attractive target for the development of probiotic and prebiotic interventions tailored to enhancethe host’s natural defences against infection.

scholarly journals In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor

2003 ◽  
Vol 77 (6) ◽  
pp. 3669-3679 ◽  
Author(s):  
Caterina Trozzi ◽  
Linda Bartholomew ◽  
Alessandra Ceccacci ◽  
Gabriella Biasiol ◽  
Laura Pacini ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Serine Protease ◽  
In Vitro Selection ◽  
Three Dimensional ◽  
Host Cells ◽  
Dimensional Structure ◽  
In Vitro Systems

ABSTRACT The hepatitis C virus (HCV) serine protease is necessary for viral replication and represents a valid target for developing new therapies for HCV infection. Potent and selective inhibitors of this enzyme have been identified and shown to inhibit HCV replication in tissue culture. The optimization of these inhibitors for clinical development would greatly benefit from in vitro systems for the identification and the study of resistant variants. We report the use HCV subgenomic replicons to isolate and characterize mutants resistant to a protease inhibitor. Taking advantage of the replicons' ability to transduce resistance to neomycin, we selected replicons with decreased sensitivity to the inhibitor by culturing the host cells in the presence of the inhibitor and neomycin. The selected replicons replicated to the same extent as those in parental cells. Sequence analysis followed by transfection of replicons containing isolated mutations revealed that resistance was mediated by amino acid substitutions in the protease. These results were confirmed by in vitro experiments with mutant enzymes and by modeling the inhibitor in the three-dimensional structure of the protease.

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.

The ultrastructure of Candida albicans infections

1981 ◽  
Vol 27 (11) ◽  
pp. 1156-1164 ◽  
Author(s):  
Thomas J. Marrie ◽  
J. William Costerton
Keyword(s):  
Candida Albicans ◽  
Oral Candidiasis ◽  
Ruthenium Red ◽  
Host Cells ◽  
Yeast Cells ◽  
Positive Matrix ◽  
Urine Sediment ◽  
Bacteria Adhesion

Scrapings of Candida albicans plaques from the tongue and buccal mucosa of patients with oral candidiasis were examined electron microscopy. In addition, urine sediment from patients with infection of their catheterized urinary tracts was similar examined. Three types of C. albicans – oral epithelial cell interactions were noted: a loose adherence apparently mediated by ruthenium red positive matrix, a "tight" adherence where no space could be seen between the host and yeast cell, and invasions host cells by yeast hyphal elements. Adhesion of Candida blastospores to hyphal elements and adhesion of bacteria to Candida cells was also frequently observed.Urine sediments from patients with mixed bacteria–yeast infections demonstrated adhesion of the bacteria to the yeast cells. This phenomenon was also demonstrated in in vitro experiments and fibrous ruthenium red material invariably occupied the zo*** of adhesion.Phagocytosis of yeast by polymorphonuclear leukocytes was found in urinary, but not in oral, candidiasis. Our in vivo and vitro observations indicate that a ruthenium red positive matrix covers the surfaces involved in the yeast to yeast, yeast to ho and yeast to bacteria adhesion.

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