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1.  Glycosylation of Candida albicans Cell Wall Proteins Is Critical for Induction of Innate Immune Responses and Apoptosis of Epithelial Cells 
PLoS ONE  2012;7(11):e50518.
C. albicans is one of the most common fungal pathogen of humans, causing local and superficial mucosal infections in immunocompromised individuals. Given that the key structure mediating host-C. albicans interactions is the fungal cell wall, we aimed to identify features of the cell wall inducing epithelial responses and be associated with fungal pathogenesis. We demonstrate here the importance of cell wall protein glycosylation in epithelial immune activation with a predominant role for the highly branched N-glycosylation residues. Moreover, these glycan moieties induce growth arrest and apoptosis of epithelial cells. Using an in vitro model of oral candidosis we demonstrate, that apoptosis induction by C. albicans wild-type occurs in early stage of infection and strongly depends on intact cell wall protein glycosylation. These novel findings demonstrate that glycosylation of the C. albicans cell wall proteins appears essential for modulation of epithelial immunity and apoptosis induction, both of which may promote fungal pathogenesis in vivo.
PMCID: PMC3511564  PMID: 23226301
2.  Cytokine and Chemokine Production by Human Oral and Vaginal Epithelial Cells in Response to Candida albicans  
Infection and Immunity  2002;70(2):577-583.
Oropharyngeal and vaginal candidiases are the most common forms of mucosal fungal infections and are primarily caused by Candida albicans, a dimorphic fungal commensal organism of the gastrointestinal and lower female reproductive tracts. Clinical and experimental observations suggest that local immunity is important in host defense against candidiasis. Accordingly, cytokines and chemokines are present at the oral and vaginal mucosa during C. albicans infections. Since mucosal epithelial cells produce a variety of cytokines and chemokines in response to microorganisms and since C. albicans is closely associated with mucosal epithelial cells as a commensal, we sought to identify cytokines and/or chemokines produced by primary oral and vaginal epithelial cells and cell lines in response to C. albicans. The results showed that proinflammatory cytokines were produced by oral and/or vaginal epithelial cells at various levels constitutively with considerable interleukin-1α (IL-1α) and tumor necrosis factor alpha, but not IL-6, produced in response to C. albicans. In contrast, Th1-type (IL-12 and gamma interferon) and Th2-type-immunoregulatory (IL-10 and transforming growth factor β) cytokines and the chemokines monocyte chemoattractant protein 1 and IL-8 were produced in low to undetectable concentrations with little additional production in response to C. albicans. Taken together, these results indicate that cytokines and chemokines are variably produced by oral and vaginal epithelial cells constitutively, as well as in response to C. albicans, and are predominated by proinflammatory cytokines.
PMCID: PMC127706  PMID: 11796585
3.  Interaction of Candida albicans with Adherent Human Peripheral Blood Mononuclear Cells Increases C. albicans Biofilm Formation and Results in Differential Expression of Pro- and Anti-Inflammatory Cytokines▿ †  
Infection and Immunity  2007;75(5):2612-2620.
Monocytes and macrophages are the cell types most commonly associated with the innate immune response against Candida albicans infection. Interactions between the host immune system and Candida organisms have been investigated for planktonic Candida cells, but no studies have addressed these interactions in a biofilm environment. In this study, for the first time, we evaluated the ability of C. albicans to form biofilms in the presence or absence of adherent peripheral blood mononuclear cells (PBMCs; enriched for monocytes and macrophages by adherence). Our analyses using scanning electron and confocal scanning laser microscopy showed that the presence of PBMCs enhanced the ability of C. albicans to form biofilms and that the majority of PBMCs were localized to the basal and middle layers of the biofilm. In contrast to the interactions of PBMCs with planktonic C. albicans, where PBMCs phagocytose fungal cells, PBMCs did not appear to phagocytose fungal cells in biofilms. Furthermore, time-lapse laser microscopy revealed dynamic interactions between C. albicans and PBMCs in a biofilm. Additionally, we found that (i) only viable PBMCs influence Candida biofilm formation, (ii) cell surface components of PBMCs did not contribute to the enhancement of C. albicans biofilm, (iii) the biofilm-enhancing effect of PBMCs is mediated by a soluble factor released into the coculture medium of PBMCs with C. albicans, and (iv) supernatant collected from this coculture contained differential levels of pro- and anti-inflammatory cytokines. Our studies provide new insight into the interaction between Candida biofilm and host immune cells and demonstrate that immunocytes may influence the ability of C. albicans to form biofilms.
PMCID: PMC1865760  PMID: 17339351
4.  Transcriptional Response of Candida albicans upon Internalization by Macrophages 
Eukaryotic Cell  2004;3(5):1076-1087.
The opportunistic fungal pathogen Candida albicans is both a benign gut commensal and a frequently fatal systemic pathogen. The interaction of C. albicans with the host's innate immune system is the primary factor in this balance; defects in innate immunity predispose the patient to disseminated candidiasis. Because of the central importance of phagocytic cells in defense against fungal infections, we have investigated the response of C. albicans to phagocytosis by mammalian macrophages using genomic transcript profiling. This analysis reveals a dramatic reprogramming of transcription in C. albicans that occurs in two successive steps. In the early phase cells shift to a starvation mode, including gluconeogenic growth, activation of fatty acid degradation, and downregulation of translation. In a later phase, as hyphal growth enables C. albicans to escape from the macrophage, cells quickly resume glycolytic growth. In addition, there is a substantial nonmetabolic response imbedded in the early phase, including machinery for DNA damage repair, oxidative stress responses, peptide uptake systems, and arginine biosynthesis. Further, a surprising percentage of the genes that respond specifically to macrophage contact have no known homologs, suggesting that the organism has undergone substantial evolutionary adaptations to the commensal or pathogen lifestyle. This transcriptional reprogramming is almost wholly absent in the related, but nonpathogenic, yeast Saccharomyces cerevisiae, suggesting that these large-scale and coordinated changes contribute significantly to the ability of this organism to survive and cause disease in vivo.
PMCID: PMC522606  PMID: 15470236
5.  Mucosal Immunity and Candida albicans Infection 
Interactions between mucosal surfaces and microbial microbiota are key to host defense, health, and disease. These surfaces are exposed to high numbers of microbes and must be capable of distinguishing between those that are beneficial or avirulent and those that will invade and cause disease. Our understanding of the mechanisms involved in these discriminatory processes has recently begun to expand as new studies bring to light the importance of epithelial cells and novel immune cell subsets such as Th17 T cells in these processes. Elucidating how these mechanisms function will improve our understanding of many diverse diseases and improve our ability to treat patients suffering from these conditions. In our voyage to discover these mechanisms, mucosal interactions with opportunistic commensal organisms such as the fungus Candida albicans provide insights that are invaluable. Here, we review current knowledge of the interactions between C. albicans and epithelial surfaces and how this may shape our understanding of microbial-mucosal interactions.
PMCID: PMC3137974  PMID: 21776285
6.  Stage-Specific Sampling by Pattern Recognition Receptors during Candida albicans Phagocytosis 
PLoS Pathogens  2008;4(11):e1000218.
Candida albicans is a medically important pathogen, and recognition by innate immune cells is critical for its clearance. Although a number of pattern recognition receptors have been shown to be involved in recognition and phagocytosis of this fungus, the relative role of these receptors has not been formally examined. In this paper, we have investigated the contribution of the mannose receptor, Dectin-1, and complement receptor 3; and we have demonstrated that Dectin-1 is the main non-opsonic receptor involved in fungal uptake. However, both Dectin-1 and complement receptor 3 were found to accumulate at the site of uptake, while mannose receptor accumulated on C. albicans phagosomes at later stages. These results suggest a potential role for MR in phagosome sampling; and, accordingly, MR deficiency led to a reduction in TNF-α and MCP-1 production in response to C. albicans uptake. Our data suggest that pattern recognition receptors sample the fungal phagosome in a sequential fashion.
Author Summary
Infection by Candida albicans has increased as a result of immunosuppression associated with AIDS and organ transplantation. We assessed the role of three pattern recognition receptors, namely Dectin-1 (a beta glucan receptor), the type 3 complement receptor (CR3), and the mannose receptor, in mediating uptake of this fungus. These receptors are known to recognize structures on the C. albicans cell wall, but their exact contribution to binding and uptake is still unclear. We show that only Dectin-1 plays a major role in binding and uptake of C. albicans. Furthermore, we are the first to find that these receptors sample the internalized particle in a sequential manner; intracellular mannose receptor is recruited later and is involved in secretion of immune modulators. These findings provide a better understanding of the innate immune mechanisms involved in protection against this medically important fungal pathogen.
PMCID: PMC2583056  PMID: 19043561
7.  Th17 cells in immunity to Candida albicans 
Cell host & microbe  2012;11(5):425-435.
Our understanding of immunity to fungal pathogens has advanced considerably in recent years. Particularly significant have been the parallel discoveries in the C-type lectin receptor family and the Th effector arms of immunity, especially Th17 cells and their signature cytokine IL-17. Many of these studies have focused on the most common human fungal pathogen Candida albicans, which is typically a commensal microbe in healthy individuals but causes various disease manifestations in immunocompromised hosts, ranging from mild mucosal infections to lethal disseminated disease. Here, we discuss emerging fundamental discoveries with C. albicans that have informed our overall molecular understanding of fungal immunity. In particular, we focus on the importance of pattern recognition receptor-mediated fungal recognition and subsequent IL-17 responses in host defense against mucosal candidiasis. In light of these recent advances, we also discuss the implications for anti-cytokine biologic therapy and vaccine development.
PMCID: PMC3358697  PMID: 22607796
8.  Interactions of Candida albicans with host epithelial surfaces 
Journal of Oral Microbiology  2013;5:10.3402/jom.v5i0.22434.
Candida albicans is an opportunistic, fungal pathogen of humans that frequently causes superficial infections of oral and vaginal mucosal surfaces of debilitated and susceptible individuals. The organism is however, commonly encountered as a commensal in healthy individuals where it is a component of the normal microflora. The key determinant in the type of relationship that Candida has with its host is how it interacts with the epithelial surface it colonises. A delicate balance clearly exists between the potentially damaging effects of Candida virulence factors and the nature of the immune response elicited by the host. Frequently, it is changes in host factors that lead to Candida seemingly changing from a commensal to pathogenic existence. However, given the often reported heterogeneity in morphological and biochemical factors that exist between Candida species and indeed strains of C. albicans, it may also be the fact that colonising strains differ in the way they exploit resources to allow persistence at mucosal surfaces and as a consequence this too may affect the way Candida interacts with epithelial cells. The aim of this review is to provide an overview of some of the possible interactions that may occur between C. albicans and host epithelial surfaces that may in turn dictate whether Candida removal, its commensal persistence or infection follows.
PMCID: PMC3805843  PMID: 24155995
oral microbiology; biofilm; virulence factors; pathogenesis
9.  Live Imaging of Disseminated Candidiasis in Zebrafish Reveals Role of Phagocyte Oxidase in Limiting Filamentous Growth ▿ † ‡ 
Eukaryotic Cell  2011;10(7):932-944.
Candida albicans is a human commensal and a clinically important fungal pathogen that grows in both yeast and hyphal forms during human infection. Although Candida can cause cutaneous and mucosal disease, systemic infections cause the greatest mortality in hospitals. Candidemia occurs primarily in immunocompromised patients, for whom the innate immune system plays a paramount role in immunity. We have developed a novel transparent vertebrate model of candidemia to probe the molecular nature of Candida-innate immune system interactions in an intact host. Our zebrafish infection model results in a lethal disseminated disease that shares important traits with disseminated candidiasis in mammals, including dimorphic fungal growth, dependence on hyphal growth for virulence, and dependence on the phagocyte NADPH oxidase for immunity. Dual imaging of fluorescently marked immune cells and fungi revealed that phagocytosed yeast cells can remain viable and even divide within macrophages without germinating. Similarly, although we observed apparently killed yeast cells within neutrophils, most yeast cells within these innate immune cells were viable. Exploiting this model, we combined intravital imaging with gene knockdown to show for the first time that NADPH oxidase is required for regulation of C. albicans filamentation in vivo. The transparent and easily manipulated larval zebrafish model promises to provide a unique tool for dissecting the molecular basis of phagocyte NADPH oxidase-mediated limitation of filamentous growth in vivo.
PMCID: PMC3147414  PMID: 21551247
10.  IL-17 Signaling in Host Defense Against Candida albicans 
Immunologic Research  2011;50(2-3):181-187.
The discovery of the Th17 lineage in 2005 triggered a major change in how immunity to infectious diseases is viewed. Fungal infections, in particular, have long been a relatively understudied area of investigation in terms of the host immune response. Candida albicans is a commensal yeast that colonizes mucosal sites and skin. In healthy individuals it is non-pathogenic, but in conditions of immune deficiency, this organism can cause a variety of infections associated with considerable morbidity. Candida can also cause disseminated infections that have a high mortality rate and are a major clinical problem in hospital settings. Although immunity to Candida albicans was long considered to be mediated by Th1 cells, new data in both rodent models and in humans have revealed an essential role for the Th17 lineage, and in particular its signature cytokine IL-17.
PMCID: PMC3257840  PMID: 21717069
IL-17; Th17; Candida albicans; fungal infections; cytokine
11.  Drosophila melanogaster Thor and Response to Candida albicans Infection▿ †  
Eukaryotic Cell  2007;6(4):658-663.
We used Drosophila melanogaster macrophage-like Schneider 2 (S2) cells as a model to study cell-mediated innate immunity against infection by the opportunistic fungal pathogen Candida albicans. Transcriptional profiling of S2 cells coincubated with C. albicans cells revealed up-regulation of several genes. One of the most highly up-regulated genes during this interaction is the D. melanogaster translational regulator 4E-BP encoded by the Thor gene. Analysis of Drosophila 4E-BPnull mutant survival upon infection with C. albicans showed that 4E-BP plays an important role in host defense, suggesting a role for translational control in the D. melanogaster response to C. albicans infection.
PMCID: PMC1865646  PMID: 17277170
12.  Hyphal Guidance and Invasive Growth in Candida albicans Require the Ras-Like GTPase Rsr1p and Its GTPase-Activating Protein Bud2p 
Eukaryotic Cell  2005;4(7):1273-1286.
Candida albicans, the most prevalent fungal pathogen of humans, causes superficial mycoses, invasive mucosal infections, and disseminated systemic disease. Many studies have shown an intriguing association between C. albicans morphogenesis and the pathogenesis process. For example, hyphal cells have been observed to penetrate host epithelial cells at sites of wounds and between cell junctions. Ras- and Rho-type GTPases regulate many morphogenetic processes in eukaryotes, including polarity establishment, cell proliferation, and directed growth in response to extracellular stimuli. We found that the C. albicans Ras-like GTPase Rsr1p and its predicted GTPase-activating protein Bud2p localized to the cell cortex, at sites of incipient daughter cell growth, and provided landmarks for the positioning of daughter yeast cells and hyphal cell branches, similar to the paradigm in the model yeast Saccharomyces cerevisiae. However, in contrast to S. cerevisiae, CaRsr1p and CaBud2p were important for morphogenesis: C. albicans strains lacking Rsr1p or Bud2p had abnormal yeast and hyphal cell shapes and frequent bends and promiscuous branching along the hypha and were unable to invade agar. These defects were associated with abnormal actin patch polarization, unstable polarisome localization at hyphal tips, and mislocalized septin rings, consistent with the idea that GTP cycling of Rsr1p stabilizes the axis of polarity primarily to a single focus, thus ensuring normal cell shape and a focused direction of polarized growth. We conclude that the Rsr1p GTPase functions as a polarity landmark for hyphal guidance and may be an important mediator of extracellular signals during processes such as host invasion.
PMCID: PMC1168968  PMID: 16002653
13.  Candida albicans interactions with epithelial cells and mucosal immunity 
Candida albicans interactions with epithelial cells are critical for commensal growth, fungal pathogenicity and host defence. This review will outline our current understanding of C. albicans-epithelial interactions and will discuss how this may lead to the induction of a protective mucosal immune response.
PMCID: PMC3185145  PMID: 21801848
Candida albicans; yeast; hyphae; epithelial cells; oral; vaginal; mucosal; innate immunity; induced endocytosis; active penetration; cytokines; chemokines; commensal; pathogen
14.  Vaginal and Oral Epithelial Cell Anti-Candida Activity  
Infection and Immunity  2002;70(12):7081-7088.
Candida albicans is the causative agent of acute and recurrent vulvovaginal candidiasis (VVC), a common mucosal infection affecting significant numbers of women in their reproductive years. While any murine host protective role for cell-mediated immunity (CMI), humoral immunity, and innate resistance by neutrophils against the vaginal infection appear negligible, significant in vitro growth inhibition of Candida species by vaginal and oral epithelial cell-enriched cells has been observed. Both oral and vaginal epithelial cell anti-Candida activity has a strict requirement for cell contact to C. albicans with no role for soluble factors, and oral epithelial cells inhibit C. albicans through a cell surface carbohydrate moiety. The present study further evaluated the inhibitory mechanisms by murine vaginal epithelial cells and the fate of C. albicans by oral and vaginal epithelial cells. Similar to human oral cells, anti-Candida activity produced by murine vaginal epithelial cells is unaffected by enzymatic cleavage of cell surface proteins and lipids but sensitive to periodic acid cleavage of surface carbohydrates. Analysis of specific membrane carbohydrate moieties, however, showed no role for sulfated polysaccharides, sialic acid residues, or glucose and mannose-containing carbohydrates, also similar to oral cells. Staining for live and dead Candida in the coculture with fluorescein diacetate (FDA) and propidium iodide (PI), respectively, showed a clear predominance of live organisms, suggesting a static rather than cidal action. Together, the results suggest that oral and vaginal epithelial cells retard or arrest the growth rather than kill C. albicans through an as-yet-unidentified carbohydrate moiety in a noninflammatory manner.
PMCID: PMC133056  PMID: 12438389
15.  First Human Model of In Vitro Candida albicans Persistence within Granuloma for the Reliable Study of Host-Fungi Interactions 
PLoS ONE  2012;7(6):e40185.
The balance between human innate immune system and Candida albicans virulence signaling mechanisms ultimately dictates the outcome of fungal invasiveness and its pathology. To better understand the pathophysiology and to identify fungal virulence-associated factors in the context of persistence in humans, complex models are indispensable. Although fungal virulence factors have been extensively studied in vitro and in vivo using different immune cell subsets and cell lines, it is unclear how C. albicans survives inside complex tissue granulomas.
Methodology/Principal Finding
We developed an original model of in vitro human granuloma, reproducing the natural granulomatous response to C. albicans. Persistent granulomas were obtained when the ratio of phagocytes to fungi was high. This in vitro fungal granuloma mimics natural granulomas, with infected macrophages surrounded by helper and cytotoxic T lymphocytes. A small proportion of granulomas exhibited C. albicans hyphae. Histological and time-lapse analysis showed that C. albicans blastoconidia were located within the granulomas before hyphae formation. Using staining techniques, fungal load calculations, as well as confocal and scanning electron microscopy, we describe the kinetics of fungal granuloma formation. We provide the first direct evidence that C. albicans are not eliminated by immunocompetent cells inside in vitro human granulomas. In fact, after an initial candicidal period, the remaining yeast proliferate and persist under very complex immune responses.
Using an original in vitro model of human fungal granuloma, we herein present the evidence that C. albicans persist and grow into immunocompetent granulomatous structures. These results will guide us towards a better understanding of fungal invasiveness and, henceforth, will also help in the development of better strategies for its control in human physiological conditions.
PMCID: PMC3387014  PMID: 22768252
16.  Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells 
Infection and Immunity  2013;81(1):238-248.
Candida albicans is 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. albicans regularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses to C. albicans have 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 of C. albicans cells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grown C. albicans stimulated 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 clinical C. albicans isolates from different host niches and from different epidemiological clades. In addition, lactate-grown C. albicans cells 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 the C. albicans interaction with the innate immune system.
PMCID: PMC3536122  PMID: 23115042
17.  Dynamic, Morphotype-Specific Candida albicans β-Glucan Exposure during Infection and Drug Treatment 
PLoS Pathogens  2008;4(12):e1000227.
Candida albicans, a clinically important dimorphic fungal pathogen that can evade immune attack by masking its cell wall β-glucan from immune recognition, mutes protective host responses mediated by the Dectin-1 β-glucan receptor on innate immune cells. Although the ability of C. albicans to switch between a yeast- or hyphal-form is a key virulence determinant, the role of each morphotype in β-glucan masking during infection and treatment has not been addressed. Here, we show that during infection of mice, the C. albicans β-glucan is masked initially but becomes exposed later in several organs. At all measured stages of infection, there is no difference in β-glucan exposure between yeast-form and hyphal cells. We have previously shown that sub-inhibitory doses of the anti-fungal drug caspofungin can expose β-glucan in vitro, suggesting that the drug may enhance immune activity during therapy. This report shows that caspofungin also mediates β-glucan unmasking in vivo. Surprisingly, caspofungin preferentially unmasks filamentous cells, as opposed to yeast form cells, both in vivo and in vitro. The fungicidal activity of caspofungin in vitro is also filament-biased, as corroborated using yeast-locked and hyphal-locked mutants. The uncloaking of filaments is not a general effect of anti-fungal drugs, as another anti-fungal agent does not have this effect. These results highlight the advantage of studying host–pathogen interaction in vivo and suggest new avenues for drug development.
Author Summary
Candida is a common human commensal but disseminated candidiasis is a serious clinical problem, especially among immunocompromised patients. The innate immune system controls Candida infection, in part through the germline-encoded β-glucan receptor Dectin-1. However, during in vitro growth, Candida albicans mutes Dectin-1 recognition by cloaking its β-glucan underneath a layer of mannan. Bridging these two seemingly contradictory observations, we demonstrate that C. albicans masks β-glucan early during infection, but it becomes exposed later, allowing Dectin-1 to recognize the fungi and mediate immunity. Remarkably, treatment of mice with sub-therapeutic doses of the antifungal drug caspofungin causes exposure of β-glucan on C. albicans even when it would not be exposed naturally. We introduce a new technique for monitoring of epitope exposure during infection, which can be used to monitor the availability of any epitope for immune recognition. This technique allowed us to show that natural unmasking of β-glucan is not morphotype-specific, but drug-mediated unmasking is biased towards the invasive filamentous form of C. albicans. These results highlight the unexplored area of dynamic epitope exposure during infection and therapy, which might be targetable to enhance immune recognition and fungal clearance.
PMCID: PMC2587227  PMID: 19057660
18.  Human Antimicrobial Peptide LL-37 Inhibits Adhesion of Candida albicans by Interacting with Yeast Cell-Wall Carbohydrates 
PLoS ONE  2011;6(3):e17755.
Candida albicans is the major fungal pathogen of humans. Fungal adhesion to host cells is the first step of mucosal infiltration. Antimicrobial peptides play important roles in the initial mucosal defense against C. albicans infection. LL-37 is the only member of the human cathelicidin family of antimicrobial peptides and is commonly expressed in various tissues and cells, including epithelial cells of both the oral cavity and urogenital tract. We found that, at sufficiently low concentrations that do not kill the fungus, LL-37 was still able to reduce C. albicans infectivity by inhibiting C. albicans adhesion to plastic surfaces, oral epidermoid OECM-1 cells, and urinary bladders of female BALB/c mice. Moreover, LL-37-treated C. albicans floating cells that did not adhere to the underlying substratum aggregated as a consequence of LL-37 bound to the cell surfaces. According to the results of a competition assay, the inhibitory effects of LL-37 on cell adhesion and aggregation were mediated by its preferential binding to mannan, the main component of the C. albicans cell wall, and partially by its ability to bind chitin or glucan, which underlie the mannan layer. Therefore, targeting of cell-wall carbohydrates by LL-37 provides a new strategy to prevent C. albicans infection, and LL-37 is a useful, new tool to screen for other C. albicans components involved in adhesion.
PMCID: PMC3056723  PMID: 21448240
19.  Regulation of Innate Immune Response to Candida albicans Infections by αMβ2-Pra1p Interaction▿  
Infection and Immunity  2011;79(4):1546-1558.
Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is one of the main tasks of cells of the innate immune system, and in vitro evidence suggests that integrin αMβ2 (CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using αMβ2-KO mice and mutated strains of C. albicans in two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in αMβ2 have a reduced ability to kill C. albicans and that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of the PRA1 gene of C. albicans, the primary ligand for αMβ2, protects the fungus against leukocyte killing in vitro and in vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasion in vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by αMβ2 plays a pivotal role in determining fungal virulence and host response and protection against C. albicans infection.
PMCID: PMC3067562  PMID: 21245270
20.  Transcriptional Response of Candida albicans to Nitric Oxide and the Role of the YHB1 Gene in Nitrosative Stress and VirulenceD⃞ 
Molecular Biology of the Cell  2005;16(10):4814-4826.
Here, we investigate how Candida albicans, the most prevalent human fungal pathogen, protects itself from nitric oxide (.NO), an antimicrobial compound produced by the innate immune system. We show that exposure of C. albicans to .NO elicits a reproducible and specific transcriptional response as determined by genome-wide microarray analysis. Many genes are transiently induced or repressed by .NO, whereas a set of nine genes remain at elevated levels during .NO exposure. The most highly induced gene in this latter category is YHB1, a flavohemoglobin that detoxifies .NO in C. albicans and other microbes. We show that C. albicans strains deleted for YHB1 have two phenotypes in vitro; they are hypersensitive to .NO and they are hyperfilamentous. In a mouse model of disseminated candidiasis, a YHB1 deleted C. albicans strain shows moderately attenuated virulence, but the virulence defect is not suppressed by deletion of the host NOS2 gene. These results suggest that .NO production is not a prime determinant of virulence in the mouse tail vein model of candidiasis and that the attenuated virulence of a yhb1Δ/yhb1Δ strain is attributable to a defect other than its reduced ability to detoxify .NO.
PMCID: PMC1237085  PMID: 16030247
21.  Serologic Response to Cell Wall Mannoproteins and Proteins of Candida albicans 
Clinical Microbiology Reviews  1998;11(1):121-141.
The cell wall of Candida albicans not only is the structure in which many biological functions essential for the fungal cells reside but also is a significant source of candidal antigens. The major cell wall components that elicit a response from the host immune system are proteins and glycoproteins, the latter being predominantly mannoproteins. Both the carbohydrate and protein moieties are able to trigger immune responses. Although cell-mediated immunity is often considered to be the most important line of defense against candidiasis, cell wall protein and glycoprotein components also elicit a potent humoral response from the host that may include some protective antibodies. Proteins and glycoproteins exposed at the most external layers of the wall structure are involved in several types of interactions of fungal cells with the exocellular environment. Thus, coating of fungal cells with host antibodies has the potential to influence profoundly the host-parasite interaction by affecting antibody-mediated functions such as opsonin-enhanced phagocytosis and blocking the binding activity of fungal adhesins for host ligands. In this review, the various members of the protein and glycoprotein fraction of the C. albicans cell wall that elicit an antibody response in vivo are examined. Although a number of proteins have been shown to stimulate an antibody response, for some of these species the response is not universal. On the other hand, some of the studies demonstrate that certain cell wall antigens and anti-cell wall antibodies may be the basis for developing specific and sensitive serologic tests for the diagnosis of candidasis, particularly the disseminated form. In addition, recent studies have focused on the potential for antibodies to cell wall protein determinants to protect the host against infection. Hence, a better understanding of the humoral response to cell wall antigens of C. albicans may provide the basis for the development of (i) effective procedures for the serodiagnosis of disseminated candidiasis and (ii) novel prophylactic (vaccination) and therapeutic strategies for the management of this type of infection.
PMCID: PMC121378  PMID: 9457431
22.  HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos 
Cells of Candida albicans (C. albicans) can invade humans and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. In this context, both the host immune status and the ability of C. albicans to modulate the expression of its virulence factors are relevant aspects that drive the candidal susceptibility or resistance; in this last case, culminating in the establishment of successful infection known as candidiasis. C. albicans possesses a potent armamentarium consisting of several virulence molecules that help the fungal cells to escape of the host immune responses. There is no doubt that the secretion of aspartyl-type proteases, designated as Saps, are one of the major virulence attributes produced by C. albicans cells, since these hydrolytic enzymes participate in a wide range of fungal physiological processes as well as in different facets of the fungal-host interactions. For these reasons, Saps clearly hold promise as new potential drug targets. Corroborating this hypothesis, the introduction of new anti-human immunodeficiency virus drugs of the aspartyl protease inhibitor-type (HIV PIs) have emerged as new agents for the inhibition of Saps. The introduction of HIV PIs has revolutionized the treatment of HIV disease, reducing opportunistic infections, especially candidiasis. The attenuation of candidal infections in HIV-infected individuals might not solely have resulted from improved immunological status, but also as a result of direct inhibition of C. albicans Saps. In this article, we review updates on the beneficial effects of HIV PIs against the human fungal pathogen C. albicans, focusing on the effects of these compounds on Sap activity, growth behavior, morphological architecture, cellular differentiation, fungal adhesion to animal cells and abiotic materials, modulation of virulence factors, experimental candidiasis infection, and their synergistic actions with classical antifungal agents.
PMCID: PMC3083943  PMID: 21537366
Candida albicans; Aspartyl protease; Proteolytic inhibitors; Human immunodeficiency virus; Chemotherapy
23.  Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells 
PLoS Biology  2007;5(3):e64.
Candida albicans is the most common cause of hematogenously disseminated and oropharyngeal candidiasis. Both of these diseases are characterized by fungal invasion of host cells. Previously, we have found that C. albicans hyphae invade endothelial cells and oral epithelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the fungal surface protein and host cell receptors that mediate this process. We found that the C. albicans Als3 is required for the organism to be endocytosed by human umbilical vein endothelial cells and two different human oral epithelial lines. Affinity purification experiments with wild-type and an als3Δ/als3Δ mutant strain of C. albicans demonstrated that Als3 was required for C. albicans to bind to multiple host cell surface proteins, including N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. Furthermore, latex beads coated with the recombinant N-terminal portion of Als3 were endocytosed by Chinese hamster ovary cells expressing human N-cadherin or E-cadherin, whereas control beads coated with bovine serum albumin were not. Molecular modeling of the interactions of the N-terminal region of Als3 with the ectodomains of N-cadherin and E-cadherin indicated that the binding parameters of Als3 to either cadherin are similar to those of cadherin–cadherin binding. Therefore, Als3 is a fungal invasin that mimics host cell cadherins and induces endocytosis by binding to N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. These results uncover the first known fungal invasin and provide evidence that C. albicans Als3 is a molecular mimic of human cadherins.
Author Summary
The fungus Candida albicans is usually a harmless colonizer of human mucosal surfaces. In the mouth, it can cause oropharyngeal candidiasis, also called thrush. In hospitalized and immunocompromised patients, C. albicans can enter the blood stream and be carried throughout the body to cause a disseminated infection, which is associated with a mortality rate of up to 40%. The organism invades the epithelial cell lining of the mouth during oropharyngeal candidiasis and invades the endothelial cell lining of the blood vessels during disseminated candidiasis. We discovered that Als3, a protein expressed on the surface of C. albicans, is required for this invasion process. Cadherins on the surface of human cells normally bind other cadherins for adhesion and signaling; however, we found that Als3 also binds to cadherins on endothelial cells and oral epithelial cells, and this binding induces these host cells to take up the fungus. The structure of Als3 is predicted to be quite similar to that of the two cadherins studied, and the parameters of the binding of Als3 to either cadherin are similar to those of cadherin–cadherin binding. These results suggest that Als3 is a functional and structural mimic of human cadherins, and provide new insights into how C. albicans invades host cells.
Als3 aids the invasion of the fungal pathogenCandida albicans into human host cells by mimicking human cadherins to induce endocytosis.
PMCID: PMC1802757  PMID: 17311474
24.  Horizontal Transmission of Candida albicans and Evidence of a Vaccine Response in Mice Colonized with the Fungus 
PLoS ONE  2011;6(7):e22030.
Disseminated candidiasis is the third leading nosocomial blood stream infection in the United States and is often fatal. We previously showed that disseminated candidiasis was preventable in normal mice by immunization with either a glycopeptide or a peptide synthetic vaccine, both of which were Candida albicans cell wall derived. A weakness of these studies is that, unlike humans, mice do not have a C. albicans GI flora and they lack Candida serum antibodies. We examined the influence of C. albicans GI tract colonization and serum antibodies on mouse vaccination responses to the peptide, Fba, derived from fructose bisphosphate aldolase which has cytosolic and cell wall distributions in the fungus. We evaluated the effect of live C. albicans in drinking water and antimicrobial agents on establishment of Candida colonization of the mouse GI tract. Body mass, C. albicans in feces, and fungal-specific serum antibodies were monitored longitudinally. Unexpectedly, C. albicans colonization occurred in mice that received only antibiotics in their drinking water, provided that the mice were housed in the same room as intentionally colonized mice. The fungal strain in unintentionally colonized mice appeared identical to the strain used for intentional GI-tract colonization. This is the first report of horizontal transmission and spontaneous C. albicans colonization in mice. Importantly, many Candida-colonized mice developed serum fungal-specific antibodies. Despite the GI-tract colonization and presence of serum antibodies, the animals made antibodies in response to the Fba immunogen. This mouse model has potential for elucidating C. albicans horizontal transmission and for exploring factors that induce host defense against disseminated candidiasis. Furthermore, a combined protracted GI-tract colonization with Candida and the possibility of serum antibody responses to the presence of the fungus makes this an attractive mouse model for testing the efficacy of vaccines designed to prevent human disseminated candidiasis.
PMCID: PMC3139608  PMID: 21818288
25.  Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling 
The Journal of Clinical Investigation  2007;117(12):3664-3672.
Mammalian TLRs are central mediators of the innate immune system that instruct cells of the innate and adaptive response to clear microbial infections. Here, we demonstrate that human epithelial TLR4 directly protected the oral mucosa from fungal infection via a process mediated by polymorphonuclear leukocytes (PMNs). In an in vitro epithelial model of oral candidiasis, the fungal pathogen Candida albicans induced a chemoattractive and proinflammatory cytokine response but failed to directly modulate the expression of genes encoding TLRs. However, the addition of PMNs to the C. albicans–infected model strongly upregulated cytoplasmic and cell-surface epithelial TLR4 expression, which correlated directly with protection against fungal invasion and cell injury. C. albicans invasion and cell injury was restored by the addition of TLR4-specific neutralizing antibodies and knockdown of TLR4 using RNA interference, even in the presence of PMNs, demonstrating the direct role of epithelial TLR4 in the protective process. Furthermore, treatment with neutralizing antibodies specific for TNF-α resulted in strongly reduced TLR4 expression accompanied by augmented epithelial cell damage and fungal invasion. To our knowledge, this is the first description of such a PMN-dependent, TLR4-mediated protective mechanism at epithelial surfaces, which may provide significant insights into how microbial infections are managed and controlled in the oral mucosa.
PMCID: PMC2066194  PMID: 17992260

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