Candida albicans skin infection in diabetic patients: An updated review of pathogenesis and management.

Candida species, commensal residents of human skin, are recognized as the cause of cutaneous candidiasis across various body surfaces. Individuals with weakened immune systems, particularly those with immunosuppressive conditions, are significantly more susceptible to this infection. Diabetes mellitus, a major metabolic disorder, has emerged as a critical factor inducing immunosuppression, thereby facilitating Candida colonization and subsequent skin infections. This comprehensive review examines the prevalence of different types of Candida albicans-induced cutaneous candidiasis in diabetic patients. It explores the underlying mechanisms of pathogenicity and offers insights into recommended preventive measures and treatment strategies. Diabetes notably increases vulnerability to oral and oesophageal candidiasis. Additionally, it can precipitate vulvovaginal candidiasis in females, Candida balanitis in males, and diaper candidiasis in young children with diabetes. Diabetic individuals may also experience candidal infections on their nails, hands and feet. Notably, diabetes appears to be a risk factor for intertrigo syndrome in obese individuals and periodontal disorders in denture wearers. In conclusion, the intricate relationship between diabetes and cutaneous candidiasis necessitates a comprehensive understanding to strategize effective management planning. Further investigation and interdisciplinary collaborative efforts are crucial to address this multifaceted challenge and uncover novel approaches for the treatment, management and prevention of both health conditions, including the development of safer and more effective antifungal agents.

Plumieride as a novel anti-fungal and anti-inflammatory iridoid against superficial candidiasis in mice.

In the past few decades, there has been a notable rise in the occurrence of several types of candidiasis. Candida albicans is the most common cause of superficial fungal infections in humans. In this study, plumieride, one of the major iridoids from Plumeria obtusa L. leaves, was isolated and investigated for its potential against Candida albicans (CA)-induced dermatitis in mice. qRT-PCR was done to assess the impact of plumieride on the expression of the major virulence genes of CA. Five groups (n = 7) of adult male BALB/c mice were categorized into: group I: non-infected mice; group II: mice infected intradermally with 107-108 CFU/mL of CA; group III: CA-infected mice treated with standard fluconazole (50 mg/kg bwt.); group IV and V: CA-infected mice treated with plumieride (25- and 50 mg/kg. bwt., respectively). All the treatments were subcutaneously injected once a day for 3 days. Skin samples were collected on the 4th day post-inoculation to perform pathological, microbial, and molecular studies. The results of the in vitro study proved that plumieride has better antifungal activity than fluconazole, manifested by a wider zone of inhibition and a lower MIC. Plumieride also downregulated the expression of CA virulence genes (ALS1, Plb1, and Hyr1). CA-infected mice showed extensive dermatitis, confirmed by strong iNOS, TNF-α, IL-1ß, and NF-κB genes or immune expressions. Whereas the treatment of CA-infected mice with plumieride significantly reduced the microscopic skin lesions and modulated the expression of all measured proinflammatory cytokines and inflammatory markers in a dose-dependent manner. Plumieride interfered with the expression of C. albicans virulence factors and modulated the inflammatory response in the skin of mice infected with CA.

Antifungal Activity of Mefloquine Against Candida albicans Growth and Virulence Factors: Insights Into Mode of Action.

The antimalarial drug Mefloquine has demonstrated antifungal activity against growth and virulence factors of Candida albicans. The current study focused on the identification of Mefloquine's mode of action in C. albicans by performing cell susceptibility assay, biofilm assay, live and dead assay, propidium iodide uptake assay, ergosterol quantification assay, cell cycle study, and gene expression studies by RT-PCR. Mefloquine inhibited the virulence factors in C. albicans, such as germ tube formation and biofilm formation at 0.125 and 1 mg/ml, respectively. Mefloquine-treated cells showed a decrease in the quantity of ergosterol content of cell membrane in a concentration-dependent manner. Mefloquine (0.25 mg/ml) arrested C. albicans cells at the G2/M phase and S phase of the cell cycle thereby preventing the progression of the normal yeast cell cycle. ROS level was measured to find out oxidative stress in C. albicans in the presence of mefloquine. The study revealed that, mefloquine was found to enhance the ROS level and subsequently oxidative stress. Gene expression studies revealed that mefloquine treatment upregulates the expressions of SOD1, SOD2, and CAT1 genes in C. albicans. In vivo, the antifungal efficacy of mefloquine was confirmed in mice for systemic candidiasis and it was found that there was a decrease in the pathogenesis of C. albicans after the treatment of mefloquine in mice. In conclusion, mefloquine can be used as a repurposed drug as an alternative drug against Candidiasis.

Mitigating candidiasis with acarbose by targeting Candida albicans α-glucosidase: in-silico, in-vitro and transcriptomic approaches.

Biofilm-associated candidiasis poses a significant challenge in clinical settings due to the limited effectiveness of existing antifungal treatments. The challenges include increased pathogen virulence, multi-drug resistance, and inadequate penetration of antimicrobials into biofilm structures. One potential solution to this problem involves the development of novel drugs that can modulate fungal virulence and biofilm formation, which is essential for pathogenesis. Resistance in Candida albicans is initiated by morphological changes from yeast to hyphal form. This transition triggers a series of events such as cell wall elongation, increased adhesion, invasion of host tissues, pathogenicity, biofilm formation, and the initiation of an immune response. The cell wall is a critical interface for interactions with host cells, primarily through various cell wall proteins, particularly mannoproteins. Thus, cell wall proteins and enzymes are considered potential antifungal targets. In this regard, we explored α-glucosidase as our potential target which plays a crucial role in processing mannoproteins. Previous studies have shown that inhibition of α-glucosidase leads to defects in cell wall integrity, reduced adhesion, diminished secretion of hydrolytic enzymes, alterations in immune recognition, and reduced pathogenicity. Since α-glucosidase, primarily converts carbohydrates, our study focuses on FDA-approved carbohydrate mimic drugs (Glycomimetics) with well-documented applications in various biological contexts. Through virtual screening of 114 FDA-approved carbohydrate-based drugs, a pseudo-sugar Acarbose, emerged as a top hit. Acarbose is known for its pharmacological potential in managing type 2 diabetes mellitus by targeting α-glucosidase. Our preliminary investigations indicate that Acarbose effectively inhibits C. albicans biofilm formation, reduces virulence, impairs morphological switching, and hinders the adhesion and invasion of host cells, all at very low concentrations in the nanomolar range. Furthermore, transcriptomic analysis reveals the mechanism of action of Acarbose, highlighting its role in targeting α-glucosidase.

Differential alteration in Lactiplantibacillus plantarum subsp. plantarum quorum-sensing systems and reduced Candida albicans yeast survival and virulence gene expression in dual-species interaction.

Candida albicans (C. albicans) and Lactiplantibacillus plantarum subsp. plantarum (L. plantarum) are frequently identified in various niches, but their dual-species interaction, especially with C. albicans in yeast form, remains unclear. This study aimed to investigate the dual-species interaction of L. plantarum and C. albicans, including proliferation, morphology, and transcriptomes examined by selective agar plate counting, microscopy, and polymicrobial RNA-seq, respectively. Maintaining a stable and unchanged growth rate, L. plantarum inhibited C. albicans yeast cell proliferation but not hyphal growth. Combining optical microscopy and atomic force microscopy, cell-to-cell direct contact and co-aggregation with L. plantarum cells surrounding C. albicans yeast cells were observed during dual-species interaction. Reduced C. albicans yeast cell proliferation in mixed culture was partially due to L. plantarum cell-free culture supernatant but not the acidic environment. Upon polymicrobial transcriptomics analysis, interesting changes were identified in both L. plantarum and C. albicans gene expression. First, two L. plantarum quorum-sensing systems showed contrary changes, with the activation of lamBDCA and repression of luxS. Second, the upregulation of stress response-related genes and downregulation of cell cycle, cell survival, and cell integrity-related pathways were identified in C. albicans, possibly connected to the stress posed by L. plantarum and the reduced yeast cell proliferation. Third, a large scale of pathogenesis and virulence factors were downregulated in C. albicans, indicating the potential interruption of pathogenic activities by L. plantarum. Fourth, partial metabolism and transport pathways were changed in L. plantarum and C. albicans. The information in this study might aid in understanding the behavior of L. plantarum and C. albicans in dual-species interaction.IMPORTANCEThe anti-Candida albicans activity of Lactiplantibacillus plantarum has been explored in the past decades. However, the importance of C. albicans yeast form and the effect of C. albicans on L. plantarum had also been omitted. In this study, the dual-species interaction of L. plantarum and C. albicans was investigated with a focus on the transcriptomes. Cell-to-cell direct contact and co-aggregation with L. plantarum cells surrounding C. albicans yeast cells were observed. Upon polymicrobial transcriptomics analysis, interesting changes were identified, including contrary changes in two L. plantarum quorum-sensing systems and reduced cell survival-related pathways and pathogenesis determinants in C. albicans.

Sur7 mediates a novel pathway for PI4,5P2 regulation in C. albicans that promotes stress resistance and cell wall morphogenesis.

The human fungal pathogen Candida albicans can cause lethal systemic infections due to its ability to resist stress from the host and to undergo invasive hyphal growth. Previous studies showed that plasma membrane MCC/eisosome domains were important for virulence by promoting the ability of Sur7 to mediate normal cell wall morphogenesis and stress resistance. The sur7Δ mutant displayed abnormal clusters of PI4,5P2, suggesting that misregulation of this lipid underlies the sur7Δ phenotype. To test this, we increased PI4,5P2 levels by deleting combinations of the three PI4,5P2 5' phosphatase genes (INP51, INP52, and INP54) and found that some combinations, such as inp51Δ inp52Δ, gave phenotypes similar the sur7Δ mutant. In contrast, deleting one copy of MSS4, the gene that encodes the 5' kinase needed to create PI4,5P2, reduced the abnormal PI4,5P2 clusters and also decreased the abnormal cell wall and stress sensitive phenotypes of the sur7Δ mutant. Additional studies support a model that the abnormal PI4,5P2 patches recruit septin proteins, which in turn promote aberrant cell wall growth. These results identify Sur7 as a novel regulator of PI4,5P2 and highlight the critical role of PI4,5P2 in the regulation of C. albicans virulence properties.

The immune and microbial homeostasis determines the Candida-mast cells cross-talk in celiac disease.

Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans-MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms.

Histone deacetylase Sir2 promotes the systemic Candida albicans infection by facilitating its immune escape via remodeling the cell wall and maintaining the metabolic activity.

Histone deacetylation affects Candida albicans (C. albicans) pathogenicity by modulating virulence factor expression and DNA damage. The histone deacetylase Sir2 is associated with C. albicans plasticity and maintains genome stability to help C. albicans adapt to various environmental niches. However, whether Sir2-mediated chromatin modification affects C. albicans virulence is unclear. The purpose of our study was to investigate the effect of Sir2 on C. albicans pathogenicity and regulation. Here, we report that Sir2 is required for C. albicans pathogenicity, as its deletion affects the survival rate, fungal burden in different organs and the extent of tissue damage in a mouse model of disseminated candidiasis. We evaluated the impact of Sir2 on C. albicans virulence factors and revealed that the Sir2 null mutant had an impaired ability to adhere to host cells and was more easily recognized by the innate immune system. Comprehensive analysis revealed that the disruption of C. albicans adhesion was due to a decrease in cell surface hydrophobicity rather than the differential expression of adhesion genes on the cell wall. In addition, Sir2 affects the distribution and exposure of mannan and ß-glucan on the cell wall, indicating that Sir2 plays a role in preventing the immune system from recognizing C. albicans. Interestingly, our results also indicated that Sir2 helps C. albicans maintain metabolic activity under hypoxic conditions, suggesting that Sir2 contributes to C. albicans colonization at hypoxic sites. In conclusion, our findings provide detailed insights into antifungal targets and a useful foundation for the development of antifungal drugs. IMPORTANCE: Candida albicans (C. albicans) is the most common opportunistic fungal pathogen and can cause various superficial infections and even life-threatening systemic infections. To successfully propagate infection, this organism relies on the ability to express virulence-associated factors and escape host immunity. In this study, we demonstrated that the histone deacetylase Sir2 helps C. albicans adhere to host cells and escape host immunity by mediating cell wall remodeling; as a result, C. albicans successfully colonized and invaded the host in vivo. In addition, we found that Sir2 contributes to carbon utilization under hypoxic conditions, suggesting that Sir2 is important for C. albicans survival and the establishment of infection in hypoxic environments. In summary, we investigated the role of Sir2 in regulating C. albicans pathogenicity in detail; these findings provide a potential target for the development of antifungal drugs.

A highly conserved tRNA modification contributes to C. albicans filamentation and virulence.

tRNA modifications play important roles in maintaining translation accuracy in all domains of life. Disruptions in the tRNA modification machinery, especially of the anticodon stem loop, can be lethal for many bacteria and lead to a broad range of phenotypes in baker's yeast. Very little is known about the function of tRNA modifications in host-pathogen interactions, where rapidly changing environments and stresses require fast adaptations. We found that two closely related fungal pathogens of humans, the highly pathogenic Candida albicans and its much less pathogenic sister species, Candida dubliniensis, differ in the function of a tRNA-modifying enzyme. This enzyme, Hma1, exhibits species-specific effects on the ability of the two fungi to grow in the hypha morphology, which is central to their virulence potential. We show that Hma1 has tRNA-threonylcarbamoyladenosine dehydratase activity, and its deletion alters ribosome occupancy, especially at 37°C-the body temperature of the human host. A C. albicans HMA1 deletion mutant also shows defects in adhesion to and invasion into human epithelial cells and shows reduced virulence in a fungal infection model. This links tRNA modifications to host-induced filamentation and virulence of one of the most important fungal pathogens of humans.IMPORTANCEFungal infections are on the rise worldwide, and their global burden on human life and health is frequently underestimated. Among them, the human commensal and opportunistic pathogen, Candida albicans, is one of the major causative agents of severe infections. Its virulence is closely linked to its ability to change morphologies from yeasts to hyphae. Here, this ability is linked-to our knowledge for the first time-to modifications of tRNA and translational efficiency. One tRNA-modifying enzyme, Hma1, plays a specific role in C. albicans and its ability to invade the host. This adds a so-far unknown layer of regulation to the fungal virulence program and offers new potential therapeutic targets to fight fungal infections.

Identification of the Most Immunoreactive Antigens of Candida auris to IgGs from Systemic Infections in Mice.

The delay in making a correct diagnosis of Candida auris causes concern in the healthcare system setting, and immunoproteomics studies are important to identify immunoreactive proteins for new diagnostic strategies. In this study, immunocompetent murine systemic infections caused by non-aggregative and aggregative phenotypes of C. auris and by Candida albicans and Candida haemulonii were carried out, and the obtained sera were used to study their immunoreactivity against C. auris proteins. The results showed higher virulence, in terms of infection signs, weight loss, and histopathological damage, of the non-aggregative isolate. Moreover, C. auris was less virulent than C. albicans but more than C. haemulonii. Regarding the immunoproteomics study, 13 spots recognized by sera from mice infected with both C. auris phenotypes and analyzed by mass spectrometry corresponded to enolase, phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. These four proteins were also recognized by sera obtained from human patients with disseminated C. auris infection but not by sera obtained from mice infected with C. albicans or Aspergillus fumigatus. Spot identification data are available via ProteomeXchange with the identifier PXD049077. In conclusion, this study showed that the identified proteins could be potential candidates to be studied as new diagnostic or even therapeutic targets for C. auris.

The hyphal-specific toxin candidalysin promotes fungal gut commensalism.

The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence1-3. Here, we reveal that this paradigm does not apply to multi-kingdom communities in which a complex interplay between fungal morphology and bacteria dictates C. albicans fitness. Thus, whereas yeast-locked cells outcompete wild-type cells when gut bacteria are absent or depleted by antibiotics, hyphae-competent wild-type cells outcompete yeast-locked cells in hosts with replete bacterial populations. This increased fitness of wild-type cells involves the production of hyphal-specific factors including the toxin candidalysin4,5, which promotes the establishment of colonization. At later time points, adaptive immunity is engaged, and intestinal immunoglobulin A preferentially selects against hyphal cells1,6. Hyphal morphotypes are thus under both positive and negative selective pressures in the gut. Our study further shows that candidalysin has a direct inhibitory effect on bacterial species, including limiting their metabolic output. We therefore propose that C. albicans has evolved hyphal-specific factors, including candidalysin, to better compete with bacterial species in the intestinal niche.

Macrophage pyroptosis induced by Candida albicans.

Candida albicans (C. albicans) is a prevalent opportunistic pathogen that causes mucocutaneous and systemic infections, particularly in immunocompromised individuals. Macrophages play a crucial role in eliminating C. albicans in local and bloodstream contexts, while also regulating antifungal immune responses. However, C. albicans can induce macrophage lysis through pyroptosis, a type of regulated cell death. This process can enable C. albicans to escape from immune cells and trigger the release of IL-1ß and IL-18, which can impact both the host and the pathogen. Nevertheless, the mechanisms by which C. albicans triggers pyroptosis in macrophages and the key factors involved in this process remain unclear. In this review, we will explore various factors that may influence or trigger pyroptosis in macrophages induced by C. albicans, such as hypha, ergosterol, cell wall remodeling, and other virulence factors. We will also examine the possible immune response following macrophage pyroptosis.

Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.

The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. Here we reveal that mice lacking cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway components had improved survival following an intravenous challenge by C. albicans. Biofilm-associated C. albicans DNA packaged in extracellular vesicles triggers the cGAS-STING pathway as determined by induction of interferon-stimulated genes, IFNß production, and phosphorylation of IFN regulatory factor 3 and TANK-binding kinase 1. Extracellular vesicle-induced activation of type I IFNs was independent of the Dectin-1/Card9 pathway and did not require toll-like receptor 9. Single nucleotide polymorphisms in cGAS and STING potently altered inflammatory cytokine production in human monocytes challenged by C. albicans. These studies provide insights into the early innate immune response induced by a clinically significant fungal pathogen.

Candida albicans Promotes Oral Cancer via IL-17A/IL-17RA-Macrophage Axis.

The association between Candida albicans (C. albicans) and oral cancer (OC) has been noticed for a long time, but the mechanisms for C. albicans promoting OC are rarely explored. In this study, we determined that C. albicans infection promoted OC incidence in a 4-nitroquinoline 1-oxide (4NQO)-induced mouse tongue carcinogenesis model as well as promoted OC progression in a tongue tumor-bearing mouse model (C3H/HeN-SCC VII). We then demonstrated that tumor-associated macrophage (TAMs) infiltration was elevated during C. albicans infection. Meanwhile, the attracted TAMs polarized into M2-like macrophages with high expression of programmed death ligand 1 (PD-L1) and galectin-9 (GAL-9). Further analysis suggested that the interleukin (IL)-17A/IL-17RA pathway activated in OC cells was a contributor to the excessive TAMs infiltration in C. albicans-infected mice. Thus, we constructed IL-17A neutralization and macrophage depletion experiments in C3H/HeN-SCC VII mice to explore the role of IL-17A/IL-17RA and TAMs in OC development caused by C. albicans infection. The results showed that both IL-17A neutralization and macrophage depletion tended to reduce the TAMs number and tumor size in mice with C. albicans infection. Collectively, our finding revealed that C. albicans promoted OC development via the IL-17A/IL-17RA-macrophage axis, opening perspectives for revealing C. albicans-tumor immune microenvironment links. IMPORTANCE The relationship between fungi and cancer is gradually receiving attention. Among them, some clinical evidence has shown that Candida may be a contributor to gastrointestinal cancers, especially oral cancer. However, the underlying mechanisms for Candida promoting oral cancer need to be explored. For this reason, this study demonstrated the role of C. albicans in oral cancer development. Moreover, this study revealed the underlying mechanisms for C. albicans promoting oral cancer from the perspective of the tumor immune microenvironment.

Candida albicans-induced activation of the TGF-ß/Smad pathway and upregulation of IL-6 may contribute to intrauterine adhesion.

Iatrogenic injury to endometrial tissue is the main cause of intrauterine adhesions (IUA) and infection can also damage the endometrium. The microbiota plays an important role in the health of the female reproductive tract. However, the mechanism is still unclear. In total, 908 patients with IUA and 11,389 healthy individuals were retrospectively selected for this clinical study. Participant information including vaginal microecological results and human papillomavirus (HPV) status were collected. Univariate and multivariate logistic regression analyses were used to identify the factors related to IUA. Next, animal experiments were performed in a curettage-induced IUA rat model. After the procedure, rats in the experimental group received a vaginal infusion of a Candida albicans (C. albicans) fungal solution. On days 3, 7, and 14 after curettage and infusion, the expression levels of IL-6, fibrotic pathway-related factors (TGF-ß1, Smad 2, and COL1), and estrogen receptor (ER) and progesterone receptor (PR) in rat endometrial tissues were assessed. Fungal infection of the reproductive tract was found to be an independent risk factor for IUA (P < 0.05). The inflammatory response and degree of fibrosis were greater in rats infected with C. albicans than in the controls. The levels of IL-6, TGF-ß1, Smad 2, and COL1 expression in endometrial tissues were significantly higher in the experimental group than in the control group (P < 0.05). However, the ER and PR levels were lower in the IUA group than in the non-IUA group (P < 0.05). C. albicans infection may be related to IUA. C. albicans elicits a strong inflammatory response that can lead to more severe endometrial fibrosis.

Infecção do trato urinário por leveduras do gênero Candida ­ revisão de literatura / Urinary tract infection by yeast of the genus Candida - literature review / Infección del tracto urinario causada por levaduras del género Candida - revisión de la literatura

A ocorrência das infecções do trato urinário (ITU) causadas por leveduras do gênero Candida estão aumentando consideravelmente nas últimas décadas, sendo a Candida albicans a mais comumente diagnosticada como causadora deste tipo de infecções. Contudo, outras espécies, como exemplo da Candida tropicalis, estão emergindo como preocupantes causadores da doença. Neste sentido, o objetivo do presente trabalho é revisar os aspectos relacionados com as ITU causadas por leveduras do gênero Candida. Foi realizada uma pesquisa na base de dados PubMed, buscando artigos sobre a epidemiologia, patogenia e tratamento das ITU causadas por leveduras do gênero Candida. As espécies de Candida são os fungos patogênicos oportunistas mais relevantes causadores de infecções nosocomiais e podem causar infecção no trato urinário, tanto inferior (ureteres, bexiga e uretra) quanto superior (rins), principalmente em pacientes imunocomprometidos. Existem alguns fatores predisponentes, como gênero feminino, idade avançada, diabetes mellitus, hospitalização prolongada, imunossupressão, gravidez, hipertensão, neutropenia, cálculos renais, infecções nosocomiais, terapia antibiótica e procedimentos, como a cateterização, que atuam como facilitadores das ITU por Candida spp. A doença pode ocorrer de forma assintomática, porém, pode evoluir para casos mais graves com comprometimento sistêmico em situações de candidemia que pode causar a morte do paciente, principalmente se tratando de indivíduos imunocomprometidos. Sendo assim, devido ao risco existente, a doença não pode ser negligenciada e um diagnóstico preciso e um tratamento adequado devem ser estabelecidos.

The occurrence of urinary tract infections (UTI) caused by yeasts of the genus Candida has increased considerably in recent decades, with Candida albicans being the most commonly diagnosed as causing this type of infections. However, other species, such as Candida tropicalis, are emerging as worrisome causes of the disease. In this sense, the objective of the present paper is to review the aspects related to the UTI caused by yeasts of the genus Candida. A search was carried out in the PubMed database, searching for articles on the epidemiology, pathogenesis and treatment of UTI caused by yeasts of the genus Candida. Candida species are the most relevant opportunistic pathogenic fungi that cause nosocomial infections and can cause both lower (ureters, bladder and urethra) and upper (kidneys) urinary tract infections, especially in immunocompromised patients. There are some predisposing factors, such as female gender, advanced age, diabetes mellitus, prolonged hospitalization, immunosuppression, pregnancy, hypertension, neutropenia, kidney stones, nosocomial infections, antibiotic therapy and procedures, such as catheterization, that act as facilitators of UTI by Candida spp. The disease can occur asymptomatically, however, it can progress to more severe cases with systemic involvement in situations of candidemia that can cause the death of the patient, especially in immunocompromised individuals. Therefore, due to the existing risk, the disease cannot be neglected and an accurate diagnosis and adequate treatment must be established.

La aparición de infecciones del tracto urinario (ITU) causadas por levaduras del género Candida ha aumentado considerablemente en las últimas décadas. Candida albicans es la infección por levaduras más comúnmente diagnosticada. Sin embargo, otras especies, como la Candida tropicalis, están surgiendo como causa preocupante de la enfermedad. En este sentido, el objetivo del presente trabajo es revisar los aspectos relacionados con la ITU causada por levaduras del género Candida. Se realizó una búsqueda en la base de datos PubMed, buscando artículos sobre la epidemiología, la patogénesis y el tratamiento de la ITU causada por levaduras del género Candida. Las especies de Candida son los hongos patógenos oportunistas más relevantes que causan infecciones nosocomiales y pueden provocar infecciones del tracto urinario inferior (uréteres, vejiga y uretra) y superior (riñones), especialmente en pacientes inmunodeprimidos. Existen algunos factores predisponentes, como el sexo femenino, la edad avanzada, la diabetes mellitus, la hospitalización prolongada, la inmunosupresión, el embarazo, la hipertensión, la neutropenia, los cálculos renales, las infecciones nosocomiales, la terapia con antibióticos y los procedimientos como el cateterismo, que actúan como facilitadores de la ITU por Candida spp. La enfermedad puede presentarse de forma asintomática, pero puede evolucionar a casos más graves con afectación sistémica en situaciones de candidemia que pueden causar la muerte del paciente, especialmente en individuos inmunodeprimidos. Por lo tanto, debido al riesgo existente, no se puede descuidar la enfermedad y se debe establecer un diagnóstico preciso y un tratamiento adecuado.

Receptor-kinase EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin.

Candida albicans (C. albicans) is a dimorphic commensal human fungal pathogen that can cause severe oropharyngeal candidiasis (oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for C. albicans pathogenesis at mucosal surfaces. Candidalysin is produced in the hyphal invasion pocket and triggers cell damage responses in OECs. Candidalysin also activates multiple MAPK-based signaling events that collectively drive the production of downstream inflammatory mediators that coordinate downstream innate and adaptive immune responses. The activities of candidalysin are dependent on signaling through the epidermal growth factor receptor (EGFR). Here, we interrogated known EGFR-MAPK signaling intermediates for their roles mediating the OEC response to C. albicans infection. Using RNA silencing and pharmacological inhibition, we identified five key adaptors, including growth factor receptor-bound protein 2 (Grb2), Grb2-associated binding protein 1 (Gab1), Src homology and collagen (Shc), SH2-containing protein tyrosine phosphatase-2 (Shp2), and casitas B-lineage lymphoma (c-Cbl). We determined that all of these signaling effectors were inducibly phosphorylated in response to C. albicans. These phosphorylation events occurred in a candidalysin-dependent manner and additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs), and cellular calcium flux to activate a complete OEC response to fungal infection. Of these, Gab1, Grb2, and Shp2 were the dominant drivers of ERK1/2 activation and the subsequent production of downstream innate-acting cytokines. Together, these results identify the key adaptor proteins that drive the EGFR signaling mechanisms that underlie oral epithelial responses to C. albicans.

Plasma Membrane Phosphatidylinositol 4-Phosphate Is Necessary for Virulence of Candida albicans.

Phosphatidylinositol lipids regulate key processes, including vesicle trafficking and cell polarity. A recent study identified novel roles for phosphatidylinositol 4-phosphate (PI4P) in the plasma membrane of the fungal pathogen Candida albicans, including polarized hyphal growth and cell wall organization. Studies in other organisms were not able to separate the roles of PI4P in the plasma membrane and Golgi, but the C. albicans plasma membrane pool of PI4P could be selectively eliminated by deleting the STT4 kinase, which creates PI4P. Interestingly, stt4Δ mutants were strongly defective in disseminated candidiasis in mice but were not defective in an oral infection. This suggested that abnormal exposure of ß-glucan in the mutant cell walls increased recruitment of innate immune cells during disseminated infection, which is not expected to impact oral infection. These results highlight novel roles of PI4P and reinforce the need to test the virulence of C. albicans mutants at different host sites.

Function of the phosphatidylinositol synthase Pis1 in maintenance of endoplasmic reticulum function and pathogenicity in Candida albicans.

Candida albicans is a common conditional pathogenic fungus in the human body, and its infections have received widespread attention in recent years. Phosphatidylinositol and its derivatives have significant regulatory effects on many physiological processes, such as cell metabolism and growth. In this study, we identified and studied the function of the phosphatidylinositol synthase Pis1 in Candida albicans. The protein has a conserved CAPT motif and multiple transmembrane domains. GFP tagging revealed that Pis1 was located at the endoplasmic reticulum (ER). The PIS1 knockout mutant was constructed using an induction system regulated by the MET3 promoter. Growth assays showed that PIS1 is an essential gene for normal growth of Candida albicans. Overexpression of PIS1 led to high sensitivity to both ER stress and cell wall stress, and down-regulated expression of the genes involved in ER stress response and maintenance of cell wall integrity. Interestingly, PIS1 overexpression enhanced secretion of the extracellular hydrolases. Virulence assays further revealed that PIS1 overexpression increased the fungal virulence, leading to quicker death of the fungus-infected mice and more severe fungal burden in the mouse kidneys. In summary, Pis1 is involved in ER stress response, maintenance of cell wall integrity, and pathogenicity of Candida albicans.

Candida albicans Infections: a novel porcine wound model to evaluate treatment efficacy.

Candida albicans is a common cause of opportunistic mycoses worldwide and a major contributor in wound infections. The purpose of this study was to establish a fungal wound model and analyze the effects of a common antifungal agent against the proliferation of three C. albicans strains. Second degree burns were created, and then inoculated with one of three different C. albicans ATCC strains: 10261 reference strain, 64550 fluconazole resistant and 26310 fluconazole sensitive. After fungal inoculation, every wound was covered with dressings for 4 h to allow fungal colonization on every wound bed. After 4 h, the dressings were removed, and each wound was treated either once or twice daily with a topical terbinafine hydrochloride or left untreated. On days 2, 4 and 7 post inoculation, three wounds from each treatment group were scrub cultured and quantified. On day 2, wounds infected with the sensitive strains 26310 and 10261 and treated twice showed a significant reduction when compared against those infected wounds receiving once daily treatment. On day 4, wounds which were infected with C. albicans fluconazole sensitive (ATCC 26310) showed a significant reduction in fungal cell counts with treatment applied twice daily. A significant reduction in the colony counts was exhibited in all three strains at the seventh day with active as compared to the non-treated wounds. Twice daily treatment resulted in a lower fungal count than once daily treatment. Neither treatment was able to entirely eradicate C. albicans during the duration of this study. Establishing a reliable fungal wound model will help in the translational goal of identifying new antifungal that could be used clinically by wound care providers.