The profile of chronic hyperplastic candidiasis: a clinico-pathological study.

The aims of this study were investigation of clinical presentation, systemic factors, and long-term malignant transformation rate in chronic hyperplastic candidiasis versus leukoplakia. This is a retrospective case-controlled study of cases with chronic hyperplastic candidiasis and leukoplakia without dysplasia, diagnosed between 2000 and 2013. A database was created, and all additional biopsies from the same cases were searched up to 2022, for records of oral malignant transformation. Associations between microscopic diagnoses and clinical features of lesions and clinical outcomes of patients were performed. A study database included 116 patients, allocated to the group diagnosed with chronic hyperplastic candidiasis (CHC-group, 62) and to the group of leukoplakia without dysplasia (LKP-group, 54). Tongue and buccal mucosa were most frequently recorded in both groups. In CHC-group, significantly fewer cases presented as white lesions compared to LKP-group (P < 0.001); more were ulcerated or exophytic (P = 0.006 and P = 0.003, respectively). History of head and neck malignancy was significantly more frequent in CHC-group (P = 0.005), as were chemotherapy, (P = 0.019) radiotherapy (P = 0.0265), and immune-related conditions (P = 0.03). Within the follow-up period (2000-2022), in CHC-group, two cases (3.2%) had malignant transformation at the site of original biopsy, one was recurrence of previous carcinoma. In LKP-group, two cases (3.7%) had newly diagnosed carcinoma and one at the site of original biopsy; no significant differences were found between groups. In conclusion, medical background of immune-related conditions, head and neck malignancy, radiotherapy, and chemotherapy may play a role in predisposing for chronic hyperplastic candidiasis. Malignant transformation rate within CHC-group was low, and similar to that within LKP-group, representing a lower transformation rate than expected.

Expression Profiles of GILZ and Annexin A1 in Human Oral Candidiasis and Lichen Planus.

Adrenal glands are the major source of glucocorticoids, but recent studies indicate tissue-specific production of cortisol, including that in the oral mucosa. Both endogenous and exogenous glucocorticoids regulate the production of several proteins, including the glucocorticoid-induced leucine zipper (GILZ) and Annexin A1, which play important roles in the regulation of immune and inflammatory responses. Common inflammation-associated oral conditions include lichen planus and candidiasis, but the status of GILZ and Annexin A1 in these human conditions remains to be established. Accordingly, archived paraffin-embedded biopsy samples were subjected to immunohistochemistry to establish tissue localization and profile of GILZ and Annexin A1 coupled with the use of hematoxylin-eosin stain for histopathological assessment; for comparison, fibroma specimens served as controls. Histopathological examination confirmed the presence of spores and pseudohyphae for oral candidiasis (OC) specimens and marked inflammatory cell infiltrates for both OC and oral lichen planus (OLP) specimens compared to control specimens. All specimens displayed consistent and prominent nuclear staining for GILZ throughout the full thickness of the epithelium and, to varying extent, for inflammatory infiltrates and stromal cells. On the other hand, a heterogeneous pattern of nuclear, cytoplasmic, and cell membrane staining was observed for Annexin A1 for all specimens in the suprabasal layers of epithelium and, to varying extent, for inflammatory and stromal cells. Semi-quantitative analyses indicated generally similar fractional areas of staining for both GILZ and Annexin A1 among the groups, but normalized staining for GILZ, but not Annexin A1, was reduced for OC and OLP compared to the control specimens. Thus, while the cellular expression pattern of GILZ and Annexin A1 does not differentiate among these conditions, differential cellular profiles for GILZ vs. Annexin A1 are suggestive of their distinct physiological functions in the oral mucosa.

Activation of EphA2-EGFR signaling in oral epithelial cells by Candida albicans virulence factors.

During oropharyngeal candidiasis (OPC), Candida albicans invades and damages oral epithelial cells, which respond by producing proinflammatory mediators that recruit phagocytes to foci of infection. The ephrin type-A receptor 2 (EphA2) detects ß-glucan and plays a central role in stimulating epithelial cells to release proinflammatory mediators during OPC. The epidermal growth factor receptor (EGFR) also interacts with C. albicans and is known to be activated by the Als3 adhesin/invasin and the candidalysin pore-forming toxin. Here, we investigated the interactions among EphA2, EGFR, Als3 and candidalysin during OPC. We found that EGFR and EphA2 constitutively associate with each other as part of a heteromeric physical complex and are mutually dependent for C. albicans-induced activation. Als3-mediated endocytosis of a C. albicans hypha leads to the formation of an endocytic vacuole where candidalysin accumulates at high concentration. Thus, Als3 potentiates targeting of candidalysin, and both Als3 and candidalysin are required for C. albicans to cause maximal damage to oral epithelial cells, sustain activation of EphA2 and EGFR, and stimulate pro-inflammatory cytokine and chemokine secretion. In the mouse model of OPC, C. albicans-induced production of CXCL1/KC and CCL20 is dependent on the presence of candidalysin and EGFR, but independent of Als3. The production of IL-1α and IL-17A also requires candidalysin but is independent of Als3 and EGFR. The production of TNFα requires Als1, Als3, and candidalysin. Collectively, these results delineate the complex interplay among host cell receptors EphA2 and EGFR and C. albicans virulence factors Als1, Als3 and candidalysin during the induction of OPC and the resulting oral inflammatory response.

Candida albicans Interaction with Oral Epithelial Cells: Adhesion , Invasion, and Damage Assays.

Microbial interactions with epithelial barriers are important steps preceding disease. Infections with Candida albicans are no exception. This opportunistic fungus, commonly harmlessly residing in close proximity to human epithelia, can shift to a more pathogenic form, can invade tissues, and cause disease. Pathogenesis, in C. albicans as well as in many other microorganisms, is characterized by three important steps: adhesion to-, invasion into-, and damage of host cells. In this book chapter, we describe three well-established protocols that allow us to differentially stain C. albicans cells adhering to and invading into host cells, therefore allowing quantifications of such processes. We also describe a common host cell cytotoxicity assay that employs a commercial kit, adapted to C. albicans.

Histopathologic aspects of the so-called chronic hyperplastic candidiasis: An analysis of 36 cases.

BACKGROUND: The present study aimed to analyze the histopathologic aspects of cases diagnosed as chronic hyperplastic candidiasis (CHC) in an oral pathology service, pointing out the most important features found. METHODS: All cases histopathologically diagnosed as CHC between 2002 and 2018 were retrieved from the files of the service. Data of the patients and the lesions were collected. Histopathological analysis was performed to evaluate the microscopic characteristics and the amount of Candida present. RESULTS: Thirty-six cases of CHC were retrieved. Women were more affected and there was a predilection for Whites. Most lesions appeared as a nodule or a white plaque, asymptomatic, on the tongue or buccal mucosa. Histopathologically, statistical significance was noted for the presence of epithelial hyperplasia, exocytosis, and mononuclear inflammatory infiltrate. Interestingly, only the association between dysplasia and the amount of fungus was noted. CONCLUSIONS: CHC appears to be a distinct entity presenting typical histopathologic aspects. CHC might even show epithelial dysplasia. In those cases, the presence of a large amount of Candida together with other histopathological features should lead to the diagnosis of CHC and subsequent treatment. However, close follow up is important.

Atividade antifúngica e potencial antibiofiome do extrato hidroetanólico de Spondias mombin L. e de suas frações frente a leveduras do gênero Candida / Antifungal activity and antibiofiome potential of the hydroethanolic extract of Spondias mombin L. and its fractions against yeasts of the genus Candida

A Candidose é uma patologia que pode ter manifestações locais e também sistêmicas e acontece pela proliferação de fungos do gênero Candida. O tratamento desta patologia é realizado com antifúngicos mas, devido a resistência dos fungos causadores desta enfermidade se faz necessário conhecer outros antifúngicos. A ação antimicrobiana do extrato hidroetanólico de Spondias mombin L. já é conhecida e é fundamental que seja pesquisado a atividade antibiofilme das substâncias, uma vez que estes fungos causam adoecimento quando se acumulam e proliferam. Sabendo disso é que o presente estudo teve por objetivo principal investigar a ação antifúngica e antibiofilme do extrato hidroetanólico (EH) de Spondias mombin L. e das frações de taninos, flavonoides e ácidos fenólicos, frente a fungos do gênero Candida, de importância clínica. Para isto, determinou-se a concentração inibitória mínima por meio do uso de discos e pela técnica da microdiluição em caldo, concentração inibitória mínima de aderência, determinação da curva de morte dos fungos e atividade antibiofilme das frações de ácidos fenólicos, flavonoides e tanino, frente aos fungos Candida albicans, Candida tropicalis, Candida Krusei e Candida Glabrata, utilizando como controle positivo a Nistatina (100.000 UI), em triplicata. Foi visto que, a atividade antifúngica e antibiofilme do EH e de suas frações analisadas existe, porém, quando comparamos as frações com o EH este último apresentou melhor atividade em suas maiores concentrações (500 µg/mL e 250 µg/mL) e quando traçamos o comparativo entre a ação antifúngica e antibiofilme das substâncias testadas e do grupo controle, tivemos melhores resultados do grupo controle frente aos fungos testados. Desta forma foi possível concluir que o extrato hidroetanólico apresentam resultados superiores de atividade antifúngica frente a todos os microrganismos testados, exceto C. krusei e antibiofilme frente a, pelo menos, uma das espécies de Candida e que este extrato teve resultados muito semelhantes e, por vezes, superior ao grupo controle (AU).

Candidosis is a pathology that can have local as well as systemic manifestations and happens due to the proliferation of fungi of the Candida genus. The treatment of this pathology is carried out with antifungal agents, but due to the resistance of the fungi that cause this disease, it is necessary to know other antifungal agents. The antimicrobial action of the hydroethanolic extract of Spondias mombin L. is already known and it is essential that the antibiofilm activity of the substances be researched, since these fungi cause illness when they accumulate and proliferate. Knowing that, this study aimed to investigate the antifungal and antibiofilm action of the hydroethanolic extract (EH) of Spondias mombin L. and its fractions, against fungi of the genus Candida, of clinical importance. For this, the minimum inhibitory concentration was determined through the use of disks and the technique of microdilution in broth, minimum inhibitory concentration of adhesion, determination of the fungal death curve and antibiofilm activity of the fractions of phenolic acids, flavonoids and tannin, against the fungi Candida albicans, Candida tropicalis, Candida Krusei and Candida Glabrata, using nystatin (100,000 IU) as a positive control, in triplicate. It was seen that the antifungal and antibiofilm activity of EH and its analyzed fractions exists, however, when we compare the fractions with EH, the latter showed better activity at its highest concentrations (500 µg/mL e 250 µg/mL) and when we draw the comparison between the antifungal and antibiofilm action of the tested substances and the control group, we had better results than the control group against the tested fungi. Thus, it was possible to conclude that the hydroethanolic extract presented superior results of antifungal activity against all tested microorganisms, except C. krusei and antibiofilm against at least one of the Candida species and that this extract had very similar results and, for times higher than the control group (AU).

Effect of probiotic bacteria on oral Candida in head- and neck-radiotherapy patients: A randomized clinical trial.

OBJECTIVE: The aim of the study is to assess the effect of probiotic bacteria on oral Candida counts in cancer patients who are undergoing head- and neck-radiotherapy in a tertiary care center. STUDY DESIGN: The study was a randomized clinical trial including 90 patients who just completed head- and neck-radiotherapy. MATERIALS AND METHODS: Participants were randomly allocated into three equal sized groups, i.e., probiotics group, candid group, and combination groups. Oral rinse samples of the patients were collected before and after the intervention for the identification of Candida. The samples were incubated on Sabouraud's Dextrose Agar with Chloramphenicol at 37°C for 48 h, to assess the counts of colony-forming units/milliliter (CFU/ml) of Candida in saliva, and further on chrome agar plates to identify the Candida spp. Data were analyzed using mixed ANOVA to compare mean CFU/ml of Candida among three groups before and after the intervention. RESULTS: A total of 86 patients were included in the final analysis and there was a statistically significant reduction in mean Candida spp. Counts (CFU/ml) after intervention in all the three groups (P = 0.000) and significant reductions identified in both probiotic and combination therapy groups. Apart from reduction in Candida albicans, significant decrease in Candida glabrata and Candida tropicalis was observed after probiotics usage compared to other groups. CONCLUSIONS: The present study suggests that probiotic bacteria were effective in reducing oral Candida spp which can be recommended alone or in combination with traditional antifungal agents for effective reduction in oral Candida in head- and neck-radiotherapy patients.

The Interleukin (IL) 17R/IL-22R Signaling Axis Is Dispensable for Vulvovaginal Candidiasis Regardless of Estrogen Status.

Candida albicans, a ubiquitous commensal fungus that colonizes human mucosal tissues and skin, can become pathogenic, clinically manifesting most commonly as oropharyngeal candidiasis and vulvovaginal candidiasis (VVC). Studies in mice and humans convincingly show that T-helper 17 (Th17)/interleukin 17 (IL-17)-driven immunity is essential to control oral and dermal candidiasis. However, the role of the IL-17 pathway during VVC remains controversial, with conflicting reports from human data and mouse models. Like others, we observed induction of a strong IL-17-related gene signature in the vagina during estrogen-dependent murine VVC. As estrogen increases susceptibility to vaginal colonization and resulting immunopathology, we asked whether estrogen use in the standard VVC model masks a role for the Th17/IL-17 axis. We demonstrate that mice lacking IL-17RA, Act1, or interleukin 22 showed no evidence for altered VVC susceptibility or immunopathology, regardless of estrogen administration. Hence, these data support the emerging consensus that Th17/IL-17 axis signaling is dispensable for the immunopathogenesis of VVC.

Candidiasis Causing Vocal Fold Leukoplakia: Review of Clinical and Pathological Results of 289 Cases With Vocal Fold Leukoplakia.

OBJECTIVE: In laryngology practice, vocal fold leukoplakia is frequently evaluated by suspension laryngoscopy and biopsy examination upon the patient's complaints of hoarseness and dysphonia. The purpose of the present study is to investigate and analyze risk factors, diagnosis, treatment, and follow-up results of cases with Candida leukoplakia. STUDY DESIGN: Retrospective case control study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Patients with a diagnosis of vocal fold leukoplakia who underwent direct laryngoscopy and biopsy between 2007 and 2017 and diagnosed as candida or noncandida in their histopathology were assigned into 2 groups. Then they were compared in terms of their demographic characteristics, predisposing factors, diagnosis, treatment, and follow-up results. RESULTS: Of the 289 vocal fold leukoplakia cases, 36 were candida, and 253 were noncandida. The mean age of the patients with Candida leukoplakia was 60.86 years. As for the age groups, the largest group (26.1%) was in the seventh decade (P < .001). The use of inhaled corticosteroids was a significant risk factor (P < .001). For their medical therapy, the patients were administered fluconazole 200 mg per day for 3 weeks, and the treatment yielded successful results in 91.66% of them. In 5 of the patients, candida leukoplakia and superficial epithelial dysplasia were observed, and no malignant transformation was observed during a mean follow-up of 28 ± 13 months. CONCLUSION: Candidiasis causing vocal fold leukoplakia is rare, and we report the findings of the largest published case series to date. Eliminating predisposing factors and administrating oral fluconazole 200 mg for 3 weeks are sufficient for medical treatment.

Candida albicans induces mucosal bacterial dysbiosis that promotes invasive infection.

Infectious complications are a common cause of morbidity and mortality in cancer patients undergoing chemotherapy due to increased risk of oral and gastrointestinal candidiasis, candidemia and septicemia. Interactions between C. albicans and endogenous mucosal bacteria are important in understanding the mechanisms of invasive infection. We published a mouse intravenous chemotherapy model that recapitulates oral and intestinal mucositis, and myelosuppression in patients receiving 5-fluorouracil. We used this model to study the influence of C. albicans on the mucosal bacterial microbiome and compared global community changes in the oral and intestinal mucosa of the same mice. We validated 16S rRNA gene sequencing data by qPCR, in situ hybridization and culture approaches. Mice receiving both 5Fu and C. albicans had an endogenous bacterial overgrowth on the oral but not the small intestinal mucosa. C. albicans infection was associated with loss of mucosal bacterial diversity in both sites with indigenous Stenotrophomonas, Alphaproteobacteria and Enterococcus species dominating the small intestinal, and Enterococcus species dominating the oral mucosa. Both immunosuppression and Candida infection contributed to changes in the oral microbiota. Enterococci isolated from mice with oropharyngeal candidiasis were implicated in degrading the epithelial junction protein E-cadherin and increasing the permeability of the oral epithelial barrier in vitro. Importantly, depletion of these organisms with antibiotics in vivo attenuated oral mucosal E-cadherin degradation and C. albicans invasion without affecting fungal burdens, indicating that bacterial community changes represent overt dysbiosis. Our studies demonstrate a complex interaction between C. albicans, the resident mucosal bacterial microbiota and the host environment in pathogenesis. We shed significant new light on the role of C. albicans in shaping resident bacterial communities and driving mucosal dysbiosis.

Iron Chelator Deferasirox Reduces Candida albicans Invasion of Oral Epithelial Cells and Infection Levels in Murine Oropharyngeal Candidiasis.

Candida albicans, the causative agent of mucosal infections, including oropharyngeal candidiasis (OPC), as well as bloodstream infections, is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off-label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence, while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron limitation using deferasirox (an FDA-approved iron chelator for the treatment of patients with iron overload) during murine OPC and assessed deferasirox-treated C. albicans for its interaction with human oral epithelial (OE) cells, neutrophils, and antimicrobial peptides. Therapeutic deferasirox treatment significantly reduced salivary iron levels, while a nonsignificant reduction in the fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model resulted in a significant reduction in the number of C. albicans CFU per gram of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans cells harvested from the tongues of animals undergoing preventive treatment had the differential expression of 106 genes, including those involved in iron metabolism, adhesion, and the response to host innate immunity. Moreover, deferasirox-treated C. albicans cells had a 2-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress) and reduced adhesion to and invasion of OE cells in vitro Thus, deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence.

A single-center 18-year experience with oral candidiasis in Brazil: a retrospective study of 1,534 cases.

Despite the large number of published studies about oral candidiasis and associated risk factors, reports of large single-center retrospective studies on the prevalence of oral candidiasis, risk factors, and the oral candidiasis types diagnosed more frequently in oral diagnostic reference centers are scarce. The objective of the present study was to retrospectively survey the demographic and clinical profiles of 1,534 patients diagnosed with candidiasis and treated at the Center for Diagnosis of Oral Diseases (CDOD), Pelotas Dental School, Federal University of Pelotas between 1997 and 2014. Using a retrospective, cross-sectional, epidemiological design, data on race, gender, age, systemic diseases, oral candidiasis type and location, symptoms, and harmful habits such as smoking and alcohol consumption were collected. The statistical analysis was performed using STATA version 13.1. Risk factors for chronic atrophic candidiasis (CAC) were evaluated using Poisson regression with robust variance (p ≤ 0.05). The majority of patients with oral candidiasis seen at the CDOD over the 18-year period of analysis were Caucasian women, aged 51-60 years, nonsmokers, and nondrinkers, with no systemic disease, and who wore some form of dental prostheses. CAC was the single most common clinical type of candidiasis detected, and the most frequently affected oral site was the palate. These data from a large single-center in Brazil agree with previous evidence about the clinical and demographic profiles of patients with oral candidiasis.

Presence of Candida spp. and candidiasis in liver transplant patients

Abstract: BACKGROUND: Candidiasis is the most common opportunistic fungal infection of the oral cavity caused by fungi of the genus Candida and usually associated with immunosuppressed individuals. OBJECTIVES: To evaluate the presence of oral candidiasis and identify the presence of Candida spp. in liver transplant recipients and assess the association between the presence of the fungus and sociodemographic variables, dietary habits and environmental exposure. METHODS: A cross-sectional study was performed with 49 patients who had undergone liver transplants at Hospital São Vicente de Paulo in Passo Fundo - RS. Patient information was collected to obtain sociodemographic data, eating habits and environmental exposure. Fungal infections were screened by oral clinical examination and the presence of Candida spp by the collection of oral samples with a sterile swab, seeded in Sabouraud Dextrose Agar, incubated at 25°C and observed at 48 hours. To identify Candida albicans, the germ tube test was performed. RESULTS: In 49 patient samples, 39% had the yeast of the genus Candida isolated and, of these patients, 12% had candidiasis, 66% of atrophic type and 34% pseudomembranous. Eleven yeast species were (58%) Candida non-albicans and eight (42%) Candida albicans. STUDY LIMITATIONS: The present study presents as a limitation the inclusion of patients in different stages of immunosuppression. CONCLUSION: The high incidence of Candida non-albicans in the oral cavity of transplant patients with a long period of transplantation is warning to a more effective control of the health of these individuals, especially those with older age.

EphA2 is an epithelial cell pattern recognition receptor for fungal ß-glucans.

Oral epithelial cells discriminate between pathogenic and non-pathogenic stimuli, and only induce an inflammatory response when they are exposed to high levels of a potentially harmful microorganism. The pattern recognition receptors (PRRs) in epithelial cells that mediate this differential response are poorly understood. Here, we demonstrate that the ephrin type-A receptor 2 (EphA2) is an oral epithelial cell PRR that binds to exposed ß-glucans on the surface of the fungal pathogen Candida albicans. Binding of C. albicans to EphA2 on oral epithelial cells activates signal transducer and activator of transcription 3 and mitogen-activated protein kinase signalling in an inoculum-dependent manner, and is required for induction of a proinflammatory and antifungal response. EphA2 -/- mice have impaired inflammatory responses and reduced interleukin-17 signalling during oropharyngeal candidiasis, resulting in more severe disease. Our study reveals that EphA2 functions as a PRR for ß-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans.

A single-center 18-year experience with oral candidiasis in Brazil: a retrospective study of 1, 534 cases

Abstract Despite the large number of published studies about oral candidiasis and associated risk factors, reports of large single-center retrospective studies on the prevalence of oral candidiasis, risk factors, and the oral candidiasis types diagnosed more frequently in oral diagnostic reference centers are scarce. The objective of the present study was to retrospectively survey the demographic and clinical profiles of 1,534 patients diagnosed with candidiasis and treated at the Center for Diagnosis of Oral Diseases (CDOD), Pelotas Dental School, Federal University of Pelotas between 1997 and 2014. Using a retrospective, cross-sectional, epidemiological design, data on race, gender, age, systemic diseases, oral candidiasis type and location, symptoms, and harmful habits such as smoking and alcohol consumption were collected. The statistical analysis was performed using STATA version 13.1. Risk factors for chronic atrophic candidiasis (CAC) were evaluated using Poisson regression with robust variance (p ≤ 0.05). The majority of patients with oral candidiasis seen at the CDOD over the 18-year period of analysis were Caucasian women, aged 51-60 years, nonsmokers, and nondrinkers, with no systemic disease, and who wore some form of dental prostheses. CAC was the single most common clinical type of candidiasis detected, and the most frequently affected oral site was the palate. These data from a large single-center in Brazil agree with previous evidence about the clinical and demographic profiles of patients with oral candidiasis.

[The relevance of Candida spp. in chronic periodontal disease]. / Vyiavlenie drozhzhepodobnykh gribov roda u patsientov s khronicheskim generalizovannym parodontitom.

The aim of the study was to assess the correlation of Candida spp. incidence in periodontal tissues with various clinical manifestations of chronic periodontal disease (CPD). Ninety patients with CPD were included in the study in which Candida spp. was evaluated in periodontal pockets content and gingival biopsy material. In severe CPD more Candida spp. were seen in gingival biopsy than in periodontal pockets (p=0.0006). Candida spp. incidence and quantity correlated directly with the disease grade showing incidence increase from 40 to 73.3% and quantity increase from 0.8±0.18 до 3.6±0.49 lg CFU/ml in light and severe CPD, correspondingly Candida spp. had statistically significant association with cyanotic gingival color (p=0.0018), tongue plaque and swelling (р=0.0042), lip exfoliation (р=0.0030), periodontal pockets depth >5 mm (р=0.0030), oral mucosa hyperemia (р=0.0157), alveolar bone destruction >1/2 of root length (р=0.0157). These data prove the relevance of Candida spp. and mycological assessment of gingival biopsy in CPD patients.

The Aryl Hydrocarbon Receptor Governs Epithelial Cell Invasion during Oropharyngeal Candidiasis.

Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (AhR), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of AhR and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that AhR plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target.IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans Our finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC.

Treatment of Oral Candidiasis Using Photodithazine®- Mediated Photodynamic Therapy In Vivo.

This study evaluated the effectiveness of antimicrobial photodynamic therapy (aPDT) in the treatment of oral candidiasis in a murine model using Photodithazine® (PDZ). This model of oral candidiasis was developed to allow the monitoring of the infection and the establishment of the aPDT treatment. Six-week-old female mice were immunosuppressed and inoculated with C. albicans to induce oral candidiasis. PDZ-mediated aPDT and nystatin treatment were carried out for 5 consecutive days with one application per day. The macroscopic evaluation of oral lesions was performed. After each treatment, the tongue was swabbed to recover C. albicans cells. Viable colonies were quantified and the number of CFU/ml determined. The animals were sacrificed 24 hours and 7 days after treatment and the tongues were surgically removed for histological analysis and analysis of inflammatory cytokines expression (IL-1, TNF-α and IL-6) by RT-qPCR. Data were analyzed by two-way ANOVA. PDZ-mediated aPDT was as effective as Nystatin (NYS group) in the inactivation of C. albicans, reducing 3 and 3.2 logs10 respectively, 24 h after treatment (p<0.05). Animals underwent PDZ-mediated aPDT showed complete remission of oral lesions, while animals treated with NYS presented partial remission of oral lesions in both periods assessed. Histological evaluation revealed mild inflammatory infiltrate in the groups treated with aPDT and NYS in both periods assessed. The aPDT induced the TNF-α expression when compared with the control (P-L-) (p<0.05), 24 h and 7 days after treatment. In summary, the murine model developed here was able to mimic the infection and PDZ-mediated aPDT was effective to treat mice with oral candidiasis.