scholarly journals Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine

2014 ◽  
Vol 82 (10) ◽  
pp. 4405-4413 ◽  
Author(s):  
Sarah E. Davis ◽  
Alex Hopke ◽  
Steven C. Minkin ◽  
Anthony E. Montedonico ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
De Novo ◽  
Invasive Disease ◽  
Innate Immune ◽  
Dependent Manner ◽  
Content Type ◽  
Immune Effector ◽  
Host Interactions ◽  
Innate Immune Effector

ABSTRACTThe virulence ofCandida albicansin a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase geneCHO1(i.e.,cho1Δ/Δ) eliminates PS and blocks thede novopathway for PE biosynthesis. In addition, thecho1Δ/Δ mutant's ability to cause invasive disease is severely compromised. Thecho1Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-typeC. albicans, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. Thecho1Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS inC. albicansresults in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.

scholarly journals Remasking of Candida albicans β-Glucan in Response to Environmental pH Is Regulated by Quorum Sensing

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Fabien Cottier ◽  
Sarah Sherrington ◽  
Sarah Cockerill ◽  
Valentina del Olmo Toledo ◽  
Stephen Kissane ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Quorum Sensing ◽  
Immune Responses ◽  
Female Reproductive Tract ◽  
Innate Immune ◽  
Immune Recognition ◽  
Innate Immune Responses ◽  
Content Type ◽  
Cell Wall Remodeling

ABSTRACT Candida albicans is a commensal yeast of the human gut which is tolerated by the immune system but has the potential to become an opportunistic pathogen. One way in which C. albicans achieves this duality is through concealing or exposing cell wall pathogen-associated molecular patterns (PAMPs) in response to host-derived environment cues (pH, hypoxia, and lactate). This cell wall remodeling allows C. albicans to evade or hyperactivate the host’s innate immune responses, leading to disease. Previously, we showed that adaptation of C. albicans to acidic environments, conditions encountered during colonization of the female reproductive tract, induces significant cell wall remodeling resulting in the exposure of two key fungal PAMPs (β-glucan and chitin). Here, we report that this pH-dependent cell wall remodeling is time dependent, with the initial change in pH driving cell wall unmasking, which is then remasked at later time points. Remasking of β-glucan was mediated via the cell density-dependent fungal quorum sensing molecule farnesol, while chitin remasking was mediated via a small, heat-stable, nonproteinaceous secreted molecule(s). Transcript profiling identified a core set of 42 genes significantly regulated by pH over time and identified the transcription factor Efg1 as a regulator of chitin exposure through regulation of CHT2. This dynamic cell wall remodeling influenced innate immune recognition of C. albicans, suggesting that during infection, C. albicans can manipulate the host innate immune responses. IMPORTANCE Candida albicans is part of the microbiota of the skin and gastrointestinal and reproductive tracts of humans and has coevolved with us for millennia. During that period, C. albicans has developed strategies to modulate the host’s innate immune responses, by regulating the exposure of key epitopes on the fungal cell surface. Here, we report that exposing C. albicans to an acidic environment, similar to the one of the stomach or vagina, increases the detection of the yeast by macrophages. However, this effect is transitory, as C. albicans is able to remask these epitopes (glucan and chitin). We found that glucan remasking is controlled by the production of farnesol, a molecule secreted by C. albicans in response to high cell densities. However, chitin-remasking mechanisms remain to be identified. By understanding the relationship between environmental sensing and modulation of the host-pathogen interaction, new opportunities for the development of innovative antifungal strategies are possible.

scholarly journals Multiple Alternative Carbon Pathways Combine To Promote Candida albicans Stress Resistance, Immune Interactions, and Virulence

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Robert B. Williams ◽  
Michael C. Lorenz
Keyword(s):  
Amino Acids ◽  
Cell Wall ◽  
Candida Albicans ◽  
Stress Resistance ◽  
Innate Immune System ◽  
Carbon Sources ◽  
Innate Immune ◽  
Content Type ◽  
Multiple Alternative ◽  
Carbon Pathways

ABSTRACT The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of the phagocyte. C. albicans rapidly adapts to the phagosome by upregulating multiple alternative carbon utilization pathways, particularly those for amino acids, carboxylic acids, and N-acetylglucosamine (GlcNAc). Here, we report that C. albicans recognizes these carbon sources both as crucial nutrients and as independent signals in its environment. Even in the presence of glucose, each carbon source promotes increased resistance to a unique profile of stressors; lactate promotes increased resistance to osmotic and cell wall stresses, amino acids increased resistance to oxidative and nitrosative stresses, and GlcNAc increased resistance to oxidative stress and caspofungin, while all three alternative carbon sources have been shown to induce resistance to fluconazole. Moreover, we show mutants incapable of utilizing these carbon sources, in particular, strains engineered to be defective in all three pathways, are significantly attenuated in both macrophage and mouse models, with additive effects observed as multiple carbon pathways are eliminated, suggesting that C. albicans simultaneously utilizes multiple carbon sources within the macrophage phagosome and during disseminated candidiasis. Taking the data together, we propose that, in addition to providing energy to the pathogen within host environments, alternative carbon sources serve as niche-specific priming signals that allow C. albicans to recognize microenvironments within the host and to prepare for stresses associated with that niche, thus promoting host adaptation and virulence. IMPORTANCE Candida albicans is a fungal pathogen and a significant cause of morbidity and mortality, particularly in people with defects, sometimes minor ones, in innate immunity. The phagocytes of the innate immune system, particularly macrophages and neutrophils, generally restrict this organism to its normal commensal niches, but C. albicans shows a robust and multifaceted response to these cell types. Inside macrophages, a key component of this response is the activation of multiple pathways for the utilization of alternative carbon sources, particularly amino acids, carboxylic acids, and N-acetylglucosamine. These carbon sources are key sources of energy and biomass but also independently promote stress resistance, induce cell wall alterations, and affect C. albicans interactions with macrophages. Engineered strains incapable of utilizing these alternative carbon pathways are attenuated in infection models. These data suggest that C. albicans recognizes nutrient composition as an indicator of specific host environments and tailors its responses accordingly.

scholarly journals β-(1,3)-Glucan Unmasking in Some Candida albicans Mutants Correlates with Increases in Cell Wall Surface Roughness and Decreases in Cell Wall Elasticity

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Sahar Hasim ◽  
David P. Allison ◽  
Scott T. Retterer ◽  
Alex Hopke ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune System ◽  
Innate Immune System ◽  
Fungal Infections ◽  
Innate Immune ◽  
Surface Topology ◽  
Wild Type ◽  
Content Type ◽  
Cell Wall Elasticity

ABSTRACT Candida albicans is among the most common human fungal pathogens, causing a broad range of infections, including life-threatening systemic infections. The cell wall of C. albicans is the interface between the fungus and the innate immune system. The cell wall is composed of an outer layer enriched in mannosylated glycoproteins (mannan) and an inner layer enriched in β-(1,3)-glucan and chitin. Detection of C. albicans by Dectin-1, a C-type signaling lectin specific for β-(1,3)-glucan, is important for the innate immune system to recognize systemic fungal infections. Increased exposure of β-(1,3)-glucan to the immune system occurs when the mannan layer is altered or removed in a process called unmasking. Nanoscale changes to the cell wall during unmasking were explored in live cells with atomic force microscopy (AFM). Two mutants, the cho1Δ/Δ and kre5Δ/Δ mutants, were selected as representatives that exhibit modest and strong unmasking, respectively. Comparisons of the cho1Δ/Δ and kre5Δ/Δ mutants to the wild type reveal morphological changes in their cell walls that correlate with decreases in cell wall elasticity. In addition, AFM tips functionalized with Dectin-1 revealed that the forces of binding of Dectin-1 to all of the strains were similar, but the frequency of binding was highest for the kre5Δ/Δ mutant, decreased for the cho1Δ/Δ mutant, and rare for the wild type. These data show that nanoscale changes in surface topology are correlated with increased Dectin-1 adhesion and decreased cell wall elasticity. AFM, using tips functionalized with immunologically relevant molecules, can map epitopes of the cell wall and increase our understanding of pathogen recognition by the immune system.

scholarly journals Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

2012 ◽  
Vol 81 (1) ◽  
pp. 238-248 ◽  
Author(s):  
Iuliana V. Ene ◽  
Shih-Chin Cheng ◽  
Mihai G. Netea ◽  
Alistair J. P. Brown
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune System ◽  
Carbon Source ◽  
Immune Responses ◽  
Immune Cells ◽  
Carbon Sources ◽  
Innate Immune ◽  
Phagocytic Cells ◽  
Content Type

Candida albicansis a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status.C. albicansregularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses toC. albicanshave been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth ofC. albicanscells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grownC. albicansstimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinicalC. albicansisolates from different host niches and from different epidemiological clades. In addition, lactate-grownC. albicanscells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon theC. albicansinteraction with the innate immune system.

scholarly journals Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

2015 ◽  
Vol 83 (10) ◽  
pp. 4154-4164 ◽  
Author(s):  
Nan Gao ◽  
Fu-Shin X. Yu
Keyword(s):  
Candida Albicans ◽  
Tissue Injury ◽  
Fungal Keratitis ◽  
Innate Immune ◽  
Therapeutic Window ◽  
Minor Role ◽  
Dependent Manner ◽  
Content Type ◽  
And Function ◽  
Interfering Rna

Chitinase 3-like 1 (CHI3L1) has been shown to play a role in promoting antibacterial responses, decreasing tissue injury, and enhancing pulmonary repair. This study sought to elucidate the role of CHI3L1 in augmenting the corneal innate immune response toCandida albicansinfection in an animal model of fungal keratitis. Flagellin applied topically 24 h prior toC. albicansinoculation significantly protected the corneal fromC. albicansand induced CHI3L1 expression in C57BL/6 mouse corneas. CHI3L1, however, played a detectable but minor role in flagellin-induced protection. WhileC. albicanskeratitis was more severe in the corneas treated withChi3l1small interfering RNA (siRNA), corneas treated with recombinant CHI3L1 beforeC. albicansinoculation had markedly ameliorated keratitis, reduced fungal load, and decreased polymorphonucleocyte (PMN) infiltration in an interleukin 13 receptor α2 (IL-13Rα2)-dependent manner. CHI3L1 treatment resulted in the induction of the antimicrobial peptides β-defensin 3, CRAMP, and chemokine CXCL10 and its receptor CXCR3 in corneal epithelial cells. Importantly, CHI3L1 administered afterC. albicansinoculation also had strong protection against fungal keratitis, suggesting a therapeutic window. This is the first report demonstrating that CHI3L1 is induced during fungal infection, where it acts as an immunomodulator to promote fungal clearance and to regulate antifungal innate immune responses in the cornea.

scholarly journals High-Throughput Screening Identifies Genes Required forCandida albicansInduction of Macrophage Pyroptosis

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Teresa R. O’Meara ◽  
Kwamaa Duah ◽  
Cynthia X. Guo ◽  
Michelle E. Maxson ◽  
Ryan G. Gaudet ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune Cells ◽  
High Throughput Screening ◽  
Immune Cell ◽  
Fungal Infections ◽  
Innate Immune ◽  
Fungal Cell ◽  
Content Type ◽  
Cell Wall Remodeling

ABSTRACTThe innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example,Candida albicansundergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through whichC. albicansorchestrates this host response, we performed the first large-scale analysis ofC. albicansinteractions with mammalian immune cells. We identified 98C. albicansgenes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response toC. albicansinfection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed thatapoptosis-associatedspeck-like protein containing aCARD (ASC) oligomerization can occur prior to phagolysosomal rupture byC. albicanshyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response toC. albicansinfection.IMPORTANCECandida albicansis a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction ofC. albicansby innate immune cells, such as macrophages and neutrophils. Although someC. albicanscells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated theC. albicansgenes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact withC. albicansand may lead to effective strategies to modulate inflammation induced by fungal infections.

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 Cell Wall-Related Bionumbers and Bioestimates of Saccharomyces cerevisiae and Candida albicans

2013 ◽  
Vol 13 (1) ◽  
pp. 2-9 ◽  
Author(s):  
Frans M. Klis ◽  
Chris G. de Koster ◽  
Stanley Brul
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Wall ◽  
Candida Albicans ◽  
Cell Size ◽  
Pathogenic Fungus ◽  
Turgor Pressure ◽  
Hyphal Growth ◽  
Biological Research ◽  
Content Type ◽  
Starting Point

ABSTRACTBionumbers and bioestimates are valuable tools in biological research. Here we focus on cell wall-related bionumbers and bioestimates of the budding yeastSaccharomyces cerevisiaeand the polymorphic, pathogenic fungusCandida albicans. We discuss the linear relationship between cell size and cell ploidy, the correlation between cell size and specific growth rate, the effect of turgor pressure on cell size, and the reason why using fixed cells for measuring cellular dimensions can result in serious underestimation ofin vivovalues. We further consider the evidence that individual buds and hyphae grow linearly and that exponential growth of the population results from regular formation of new daughter cells and regular hyphal branching. Our calculations show that hyphal growth allowsC. albicansto cover much larger distances per unit of time than the yeast mode of growth and that this is accompanied by strongly increased surface expansion rates. We therefore predict that the transcript levels of genes involved in wall formation increase during hyphal growth. Interestingly, wall proteins and polysaccharides seem barely, if at all, subject to turnover and replacement. A general lesson is how strongly most bionumbers and bioestimates depend on environmental conditions and genetic background, thus reemphasizing the importance of well-defined and carefully chosen culture conditions and experimental approaches. Finally, we propose that the numbers and estimates described here offer a solid starting point for similar studies of other cell compartments and other yeast species.

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