scholarly journals Recognition and Blocking of Innate Immunity Cells by Candida albicans Chitin

2011 ◽  
Vol 79 (5) ◽  
pp. 1961-1970 ◽  
Author(s):  
Héctor M. Mora-Montes ◽  
Mihai G. Netea ◽  
Gerben Ferwerda ◽  
Megan D. Lenardon ◽  
Gordon D. Brown ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Cell Walls ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Immune Cell ◽  
Human Peripheral Blood ◽  
Immune Recognition ◽  
Cell Wall Polysaccharide ◽  
Content Type

ABSTRACTChitin is a skeletal cell wall polysaccharide of the inner cell wall of fungal pathogens. As yet, little about its role during fungus-host immune cell interactions is known. We show here that ultrapurified chitin fromCandida albicanscell walls did not stimulate cytokine production directly but blocked the recognition ofC. albicansby human peripheral blood mononuclear cells (PBMCs) and murine macrophages, leading to significant reductions in cytokine production. Chitin did not affect the induction of cytokines stimulated by bacterial cells or lipopolysaccharide (LPS), indicating that blocking was not due to steric masking of specific receptors. Toll-like receptor 2 (TLR2), TLR4, and Mincle (the macrophage-inducible C-type lectin) were not required for interactions with chitin. Dectin-1 was required for immune blocking but did not bind chitin directly. Cytokine stimulation was significantly reduced upon stimulation of PBMCs with heat-killed chitin-deficientC. albicanscells but not with live cells. Therefore, chitin is normally not exposed to cells of the innate immune system but is capable of influencing immune recognition by blocking dectin-1-mediated engagement with fungal cell walls.

scholarly journals Nanoscopic cell-wall architecture of an immunogenic ligand in Candida albicans during antifungal drug treatment

2016 ◽  
Vol 27 (6) ◽  
pp. 1002-1014 ◽  
Author(s):  
Jia Lin ◽  
Michael J. Wester ◽  
Matthew S. Graus ◽  
Keith A. Lidke ◽  
Aaron K. Neumann
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Cell Walls ◽  
Innate Immune ◽  
Immune Recognition ◽  
Cell Wall Polysaccharide ◽  
Stochastic Optical Reconstruction Microscopy ◽  
Before And After ◽  
Antifungal Chemotherapy ◽  
Optical Reconstruction

The cell wall of Candida albicans is composed largely of polysaccharides. Here we focus on β-glucan, an immunogenic cell-wall polysaccharide whose surface exposure is often restricted, or “masked,” from immune recognition by Dectin-1 on dendritic cells (DCs) and other innate immune cells. Previous research suggested that the physical presentation geometry of β-glucan might determine whether it can be recognized by Dectin-1. We used direct stochastic optical reconstruction microscopy to explore the fine structure of β-glucan exposed on C. albicans cell walls before and after treatment with the antimycotic drug caspofungin, which alters glucan exposure. Most surface-accessible glucan on C. albicans yeast and hyphae is limited to isolated Dectin-1–binding sites. Caspofungin-induced unmasking caused approximately fourfold to sevenfold increase in total glucan exposure, accompanied by increased phagocytosis efficiency of DCs for unmasked yeasts. Nanoscopic imaging of caspofungin-unmasked C. albicans cell walls revealed that the increase in glucan exposure is due to increased density of glucan exposures and increased multiglucan exposure sizes. These findings reveal that glucan exhibits significant nanostructure, which is a previously unknown physical component of the host– Candida interaction that might change during antifungal chemotherapy and affect innate immune activation.

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 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.

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 Epitope Shaving Promotes Fungal Immune Evasion

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Delma S. Childers ◽  
Gabriela Mol Avelar ◽  
Judith M. Bain ◽  
Arnab Pradhan ◽  
Daniel E. Larcombe ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Cell Surface ◽  
Immune Evasion ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Specific Cell ◽  
Immune Recognition ◽  
Content Type ◽  
Evasion Strategy

ABSTRACT The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan “masking” pathway to promote β-1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes. IMPORTANCE The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion.

scholarly journals Glucan Unmasking Identifies Regulators of Temperature-Induced Translatome Reprogramming in C. neoformans

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Amanda L. M. Bloom ◽  
David Goich ◽  
Corey M. Knowles ◽  
John C. Panepinto
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Temperature Stress ◽  
Fungal Pathogen ◽  
Cell Walls ◽  
Mapk Pathway ◽  
Regulation Of Transcription ◽  
Immune Recognition ◽  
Content Type ◽  
Signaling Modules

ABSTRACT The cell walls of fungi are critical for cellular structure and rigidity but also serve as a major communicator to alert the cell to the changing environment. In response to stresses encountered in human hosts, pathogenic fungi remodel their cell walls. Masking the β-1,3-glucan component of the cell wall is critical to escape detection by innate immune cells. We previously demonstrated that β-1,3-glucan is unmasked in response to host temperature stress when translatome reprogramming is defective in Cryptococcus neoformans. Here, we used β-1,3-glucan unmasking as an output to identify signaling modules involved both in masking and in translatome reprogramming in response to host temperature stress. We reveal that the high-osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) pathway is involved in translatome reprogramming and that mutants in this pathway display moderate unmasking when grown at 37°C. Additionally, we show that mutants of the cell wall integrity (CWI)/Mpk1 MAPK pathway extensively unmask β-1,3-glucan. While the CWI pathway does not impact translatome reprogramming, our data suggest that it may play a role in the posttranslational regulation of transcription factors that govern masking. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that causes devastating morbidity and mortality in immunocompromised individuals. It possesses several virulence factors that aid in its evasion from the host immune system, including a large polysaccharide capsule that cloaks the antigenic cell wall. Studies investigating how the cell wall is remodeled to keep this pathogen disguised in response to stress have been limited. We previously found that host temperature stress results in translatome reprogramming that is necessary for keeping the highly antigenic β-(1, 3)-glucan component masked. Our data reveal signaling modules that trigger these responses and suggest the points of regulation at which these pathways act in achieving masking. Understanding these mechanisms may allow for therapeutic manipulation that may promote the immune recognition and clearance of this fungal pathogen.

scholarly journals Elevated Chitin Content Reduces the Susceptibility of Candida Species to Caspofungin

2012 ◽  
Vol 57 (1) ◽  
pp. 146-154 ◽  
Author(s):  
Louise A. Walker ◽  
Neil A. R. Gow ◽  
Carol A. Munro
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Point Mutations ◽  
Antifungal Drugs ◽  
Cell Wall Polysaccharide ◽  
Chitin Synthesis ◽  
Fungal Cell ◽  
Content Type ◽  
Chitin Content ◽  
Compensatory Increase

ABSTRACTThe echinocandin antifungal drugs inhibit synthesis of the major fungal cell wall polysaccharide β(1,3)-glucan. Echinocandins have good efficacy againstCandida albicansbut reduced activity against otherCandidaspecies, in particularCandida parapsilosisandCandida guilliermondii. Treatment ofCandida albicanswith a sub-MIC level of caspofungin has been reported to cause a compensatory increase in chitin content and to select for sporadic echinocandin-resistantFKS1point mutants that also have elevated cell wall chitin. Here we show that elevated chitin in response to caspofungin is a common response in variousCandidaspecies. Activation of chitin synthesis was observed in isolates ofC. albicans,Candida tropicalis,C. parapsilosis, andC. guilliermondiiand in some isolates ofCandida kruseiin response to caspofungin treatment. However,Candida glabrataisolates demonstrated no exposure-induced change in chitin content. Furthermore, isolates ofC. albicans,C. krusei,C. parapsilosis, andC. guilliermondiiwhich were stimulated to have higher chitin levels via activation of the calcineurin and protein kinase C (PKC) signaling pathways had reduced susceptibility to caspofungin. Isolates containing point mutations in theFKS1gene generally had higher chitin levels and did not demonstrate a further compensatory increase in chitin content in response to caspofungin treatment. These results highlight the potential of increased chitin synthesis as a potential mechanism of tolerance to caspofungin for the major pathogenicCandidaspecies.

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.

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