scholarly journals A Fungal Transcription Regulator of Vacuolar Function Modulates Candida albicans Interactions with Host Epithelial Cells

mBio ◽  
2021 ◽  
Author(s):  
Philipp Reuter-Weissenberger ◽  
Juliane Meir ◽  
J. Christian Pérez
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Aids Patients ◽  
Content Type ◽  
Immune Systems ◽  
Transcription Regulator ◽  
Mucosal Disease ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
Oral Thrush

Candida albicans is a fungus that resides on various human mucosal surfaces. Individuals with debilitated immune systems are prone to develop C. albicans infections, which can range in severity from mucosal disease (e.g., oral thrush in AIDS patients) to life-threatening conditions (e.g., deep-seated, disseminated infections in patients undergoing organ transplants).

scholarly journals Novel Aggregation Properties of Candida albicans Secreted Aspartyl Proteinase Sap6 Mediate Virulence in Oral Candidiasis

2015 ◽  
Vol 83 (7) ◽  
pp. 2614-2626 ◽  
Author(s):  
Rohitashw Kumar ◽  
Darpan Saraswat ◽  
Swetha Tati ◽  
Mira Edgerton
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Oral Candidiasis ◽  
Oral Microbiome ◽  
Proteinase Activity ◽  
Adhesion Properties ◽  
Content Type ◽  
Oral Epithelial Cells ◽  
Oral Epithelial ◽  
Cell Cell

Candida albicans, a commensal fungus of the oral microbiome, causes oral candidiasis in humans with localized or systemic immune deficiencies. Secreted aspartic proteinases (Saps) are a family of 10 related proteases and are virulence factors due to their proteolytic activity, as well as their roles in adherence and colonization of host tissues. We found that mice infected sublingually withC. albicanscells overexpressing Sap6 (SAP6OE and a Δsap8strain) had thicker fungal plaques and more severe oral infection, while infection with the Δsap6strain was attenuated. These hypervirulent strains had highly aggregative colony structurein vitroand higher secreted proteinase activity; however, the levels of proteinase activity ofC. albicansSaps did not uniformly match their abilities to damage cultured oral epithelial cells (SCC-15 cells). Hyphal induction in cells overexpressing Sap6 (SAP6OE and Δsap8cells) resulted in formation of large cell-cell aggregates. These aggregates could be produced in germinated wild-type cells by addition of native or heat-inactivated Sap6. Sap6 bound only to germinated cells and increasedC. albicansadhesion to oral epithelial cells. The adhesion properties of Sap6 were lost upon deletion of its integrin-binding motif (RGD) and could be inhibited by addition of RGD peptide or anti-integrin antibodies. Thus, Sap6 (but not Sap5) has an alternative novel function in cell-cell aggregation, independent of its proteinase activity, to promote infection and virulence in oral candidiasis.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

scholarly journals Interactions between Candida albicans and Enterococcus faecalis in an Organotypic Oral Epithelial Model

2020 ◽  
Vol 8 (11) ◽  
pp. 1771
Author(s):  
Akshaya Lakshmi Krishnamoorthy ◽  
Alex A. Lemus ◽  
Adline Princy Solomon ◽  
Alex M. Valm ◽  
Prasanna Neelakantan
Keyword(s):  
Candida Albicans ◽  
Enterococcus Faecalis ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Surface Erosion ◽  
Host Immune System ◽  
Microbial Invasion ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
Hyphal Formation

Candida albicans as an opportunistic pathogen exploits the host immune system and causes a variety of life-threatening infections. The polymorphic nature of this fungus gives it tremendous advantage to breach mucosal barriers and cause oral and disseminated infections. Similar to C. albicans, Enterococcus faecalis is a major opportunistic pathogen, which is of critical concern in immunocompromised patients. There is increasing evidence that E. faecalis co-exists with C. albicans in the human body in disease samples. While the interactive profiles between these two organisms have been studied on abiotic substrates and mouse models, studies on their interactions on human oral mucosal surfaces are non-existent. Here, for the first time, we comprehensively characterized the interactive profiles between laboratory and clinical isolates of C. albicans (SC5314 and BF1) and E. faecalis (OG1RF and P52S) on an organotypic oral mucosal model. Our results demonstrated that the dual species biofilms resulted in profound surface erosion and significantly increased microbial invasion into mucosal compartments, compared to either species alone. Notably, several genes of C. albicans involved in tissue adhesion, hyphal formation, fungal invasion, and biofilm formation were significantly upregulated in the presence of E. faecalis. By contrast, E. faecalis genes involved in quorum sensing, biofilm formation, virulence, and mammalian cell invasion were downregulated. This study highlights the synergistic cross-kingdom interactions between E. faecalis and C. albicans in mucosal tissue invasion.

scholarly journals CX3CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

2014 ◽  
Vol 83 (3) ◽  
pp. 958-965 ◽  
Author(s):  
Timothy J. Break ◽  
Martin Jaeger ◽  
Norma V. Solis ◽  
Scott G. Filler ◽  
Carlos A. Rodriguez ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Human Population ◽  
Systemic Candidiasis ◽  
Gi Tract ◽  
Content Type ◽  
Commensal Microbiota ◽  
Interleukin 17A ◽  
Mucosal Surfaces ◽  
Bacterial Microbiota ◽  
Mucosal Candidiasis

Candida albicansis part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunisticCandidainfections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosalC. albicansinfection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 alleleCX3CR1-M280was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemicCandidainfections.

scholarly journals Candida albicans Adhesion to and Invasion and Damage of Vaginal Epithelial Cells: Stage-Specific Inhibition by Clotrimazole and Bifonazole

2011 ◽  
Vol 55 (9) ◽  
pp. 4436-4439 ◽  
Author(s):  
Betty Wächtler ◽  
Duncan Wilson ◽  
Bernhard Hube
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Antifungal Agents ◽  
Vaginal Epithelium ◽  
Specific Inhibition ◽  
Content Type ◽  
Vaginal Epithelial Cells ◽  
Specific Activities ◽  
Low Levels ◽  
Adhesion And Invasion

ABSTRACTClotrimazole and bifonazole are highly effective antifungal agents against mucosalCandida albicansinfections. Here we examined the effects of low levels of clotrimazole and bifonazole on the ability ofC. albicansto adhere, invade, and damage vaginal epithelial cells. Although adhesion and invasion were not affected, damage was greatly reduced upon azole treatment. This clearly indicates that low levels of azoles influence specific activities ofC. albicansduring distinct stages of vaginal epithelium infections.

scholarly journals Mucins Suppress Virulence Traits of Candida albicans

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Nicole L. Kavanaugh ◽  
Angela Q. Zhang ◽  
Clarissa J. Nobile ◽  
Alexander D. Johnson ◽  
Katharina Ribbeck
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Therapeutic Potential ◽  
Content Type ◽  
Environmental Signals ◽  
Healthy Humans ◽  
Normal Microbiota ◽  
Life Threatening ◽  
Main Components

ABSTRACTCandida albicansis the most prevalent fungal pathogen of humans, causing a variety of diseases ranging from superficial mucosal infections to deep-seated systemic invasions. Mucus, the gel that coats all wet epithelial surfaces, accommodatesC. albicansas part of the normal microbiota, whereC. albicansresides asymptomatically in healthy humans. Through a series ofin vitroexperiments combined with gene expression analysis, we show that mucin biopolymers, the main gel-forming constituents of mucus, induce a new oval-shaped morphology inC. albicansin which a range of genes related to adhesion, filamentation, and biofilm formation are downregulated. We also show that corresponding traits are suppressed, renderingC. albicansimpaired in forming biofilms on a range of different synthetic surfaces and human epithelial cells. Our data suggest that mucins can manipulateC. albicansphysiology, and we hypothesize that they are key environmental signals for retainingC. albicansin the host-compatible, commensal state.IMPORTANCEThe yeastCandida albicanscauses both superficial infections of the mucosa and life-threatening infections upon entering the bloodstream. However,C. albicansis not always harmful and can exist as part of the normal microbiota without causing disease. Internal body surfaces that are susceptible to infection byC. albicansare coated with mucus, which we hypothesize plays an important role in preventing infections. Here, we show that the main components of mucus, mucin glycoproteins, suppress virulence attributes ofC. albicansat the levels of gene expression and the corresponding morphological traits. Specifically, mucins suppress attachment to plastic surfaces and human cells, the transition to cell-penetrating hyphae, and the formation of biofilms (drug-resistant microbial communities). Additionally, exposure to mucins induces an elongated morphology that physically resembles the mating-competent opaque state but is phenotypically distinct. We suggest that mucins are potent antivirulence molecules that have therapeutic potential for suppressingC. albicansinfections.

scholarly journals Epithelial Cell Innate Response to Candida albicans

2011 ◽  
Vol 23 (1) ◽  
pp. 50-55 ◽  
Author(s):  
J.R. Naglik ◽  
D. Moyes
Keyword(s):  
Candida Albicans ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Fungal Pathogens ◽  
Fungal Diseases ◽  
Lymphoid Cells ◽  
Innate Response ◽  
Epithelial Surface ◽  
Immune Systems ◽  
Pathogenic Microbes

With the advent of treatments and diseases such as AIDS resulting in increasing numbers of patients with suppressed immune systems, fungal diseases are an escalating problem. Candida albicans is the most common of these fungal pathogens, causing infections in many of these patients. It is therefore important to understand how immunity to this fungus is regulated and how it might be manipulated. Although work has been done to identify the receptors, fungal moieties, and responses involved in anti- Candida immunity, most studies have investigated interactions with myeloid or lymphoid cells. Given that the first site of contact of C. albicans with its host is the mucosal epithelial surface, recent studies have begun to focus on interactions of C. albicans with this site. The results are startling yet in retrospect obvious, indicating that epithelial cells play an important role in these interactions, initiating responses and even providing a level of protection. These findings have obvious implications, not just for fungal pathogens, but also for identifying how host organisms can distinguish between commensal and pathogenic microbes. This review highlights some of these recent findings and discusses their importance in the wider context of infection and immunity.

scholarly journals Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in Mice

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Eva Pericolini ◽  
Elena Gabrielli ◽  
Mario Amacker ◽  
Lydia Kasper ◽  
Elena Roselletti ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Common Disease ◽  
Content Type ◽  
Neutrophil Influx ◽  
Caspase 1 ◽  
Vaginal Epithelial Cells ◽  
Pepstatin A ◽  
Aspartyl Proteinases

ABSTRACTVaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungusCandida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits ofC. albicansthat have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candidavaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome-dependent interleukin-1β (IL-1β) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated byC. albicansintravaginal injection, and a mutant strain lackingSAP1,SAP2, andSAP3was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1β and IL-18 production by vaginal epithelial cells, and blockade of the IL-1β receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteinsin vivoand can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells toC. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis.IMPORTANCECandidal vaginitis is an acute inflammatory disease that affects many women of fertile age, with no definitive cure and, in its recurrent forms, causing true devastation of quality of life. Unraveling the fungal factors causing inflammation is important to be able to devise novel tools to fight the disease. In an experimental murine model, we have discovered that aspartyl proteinases, particularly Sap2, may cause the same inflammatory signs of vaginitis caused by the fungus and that anti-Sap antibodies and the protease inhibitor Pepstatin A almost equally inhibit Sap- andC. albicans-induced inflammation. Sap-induced vaginitis is an early event during vaginal infection, is uncoupled from fungal growth, and requires Sap and caspase-1 enzymatic activities to occur, suggesting that Sap or products of Sap activity activate an inflammasome sensor of epithelial cells. Our data support the notion that anti-Sap antibodies could help control the essence of candidal vaginitis, i.e., the inflammatory response.

scholarly journals Candida albicans Hypha Formation and Mannan Masking of β-Glucan Inhibit Macrophage Phagosome Maturation

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Judith M. Bain ◽  
Johanna Louw ◽  
Leanne E. Lewis ◽  
Blessing Okai ◽  
Catriona A. Walls ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Fluorescent Protein ◽  
Cell Wall Composition ◽  
Live Cell ◽  
Actin Dynamics ◽  
Phagosome Maturation ◽  
Content Type ◽  
Life Threatening

ABSTRACTCandida albicansis a major life-threatening human fungal pathogen in the immunocompromised host. Host defense against systemicCandidainfection relies heavily on the capacity of professional phagocytes of the innate immune system to ingest and destroy fungal cells. A number of pathogens, includingC. albicans, have evolved mechanisms that attenuate the efficiency of phagosome-mediated inactivation, promoting their survival and replication within the host. Here we visualize host-pathogen interactions using live-cell imaging and show that viable, but not heat- or UV-killedC. albicanscells profoundly delay phagosome maturation in macrophage cell lines and primary macrophages. The ability ofC. albicansto delay phagosome maturation is dependent on cell wall composition and fungal morphology. Loss of cell wallO-mannan is associated with enhanced acquisition of phagosome maturation markers, distinct changes in Rab GTPase acquisition by the maturing phagosome, impaired hyphal growth within macrophage phagosomes, profound changes in macrophage actin dynamics, and ultimately a reduced ability of fungal cells to escape from macrophage phagosomes. The loss of cell wallO-mannan leads to exposure of β-glucan in the inner cell wall, facilitating recognition by Dectin-1, which is associated with enhanced phagosome maturation.IMPORTANCEInnate cells engulf and destroy invading organisms by phagocytosis, which is essential for the elimination of fungal cells to protect against systemic life-threatening infections. Yet comparatively little is known about what controls the maturation of phagosomes following ingestion of fungal cells. We used live-cell microscopy and fluorescent protein reporter macrophages to understand howC. albicansviability, filamentous growth, and cell wall composition affect phagosome maturation and the survival of the pathogen within host macrophages. We have demonstrated that cell wall glycosylation and yeast-hypha morphogenesis are required for disruption of host processes that function to inactivate pathogens, leading to survival and escape of this fungal pathogen from within host phagocytes. The methods employed here are applicable to study interactions of other pathogens with phagocytic cells to dissect how specific microbial features impact different stages of phagosome maturation and the survival of the pathogen or host.

Sign in / Sign up

Export Citation Format

Share Document