Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.

Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect. Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics. Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time. Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.

Interleukin inhibitors and the associated risk of candidiasis.

Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.

The inhibitory effects of carvacrol, nystatin, and their combination on oral candidiasis isolates.

BACKGROUND: Candida, a common oral microbiota, can cause opportunistic fungal infections. With rising Candida infections and limited effective antifungals, new treatments are needed. This study investigates carvacrol essential oil's effect on oral candidiasis, alone and with nystatin, compared to nystatin alone. MATERIALS AND METHODS: In this study, oral samples were collected from dental clinic patients, especially denture users. The presence of Candida was confirmed and cultured from these samples. Candidiasis was detected by observing Candida colonies. Drug sensitivity was tested on 100 positive samples. The minimum concentration of inhibition and lethality of each isolate was evaluated using nystatin and carvacrol. The results were compared using two-way analysis of variance. Finally, the minimum inhibitory concentration (MIC) of nystatin and carvacrol was calculated individually and in combination. RESULTS: The present study found that Candida albicans and non-albicans species were equally prevalent. Carvacrol showed significant biological activity against all Candida species, with an average MTT of 50.01%. The average MIC value of carvacrol was 24.96 µg/ml, indicating its potential to inhibit Candida growth. The mean Minimum Fungicidal Concentration (MFC) value of carvacrol was 23.48 µg/ml, suggesting its effectiveness in killing the fungi. CONCLUSION: The study's findings reveal that the MIC of carvacrol was significantly lower than that of nystatin and the combination of nystatin and carvacrol. This suggests that carvacrol holds potential as an effective herbal remedy for candidiasis.

Candida auris in US Correctional Facilities.

Candida auris is an emerging fungal pathogen that typically affects patients in healthcare settings. Data on C. auris cases in correctional facilities are limited but are needed to guide public health recommendations. We describe cases and challenges of providing care for 13 patients who were transferred to correctional facilities during January 2020-December 2022 after having a positive C. auris specimen. All patients had positive specimens identified while receiving inpatient care at healthcare facilities in geographic areas with high C. auris prevalence. Correctional facilities reported challenges managing patients and implementing prevention measures; those challenges varied by whether patients were housed in prison medical units or general population units. Although rarely reported, C. auris cases in persons who are incarcerated may occur, particularly in persons with known risk factors. Measures to manage cases and prevent C. auris spread in correctional facilities should address setting-specific challenges in healthcare and nonhealthcare correctional environments.

Antifungal chemosensitization through induction of oxidative stress: A model for control of candidiasis based on the Lippia origanoides essential oil.

In this work, evaluated the antifungal chemosensitizing effect of the Lippia origanoides essential oil (EO) through the induction of oxidative stress. The EO was obtained by hydrodistillation and analyzed by GC-MS. To evaluate the antifungal chemosensitizing effect through induction of oxidative stress, cultures of the model yeast Saccharomyces cerevisiae ∆ycf1 were exposed to sub-inhibitory concentrations of the EO, and the expression of genes known, due be overexpressed in response to oxidative and mutagenic stress was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) method. Carvacrol and thymol were identified as the main components. The EO was effective in preventing or reducing the growth of the microorganisms tested. The gene expression profiles showed that EO promoted changes in the patterns of expression of genes involved in oxidative and mutagenic stress resistance. The combined use of the L. origanoides EO with fluconazole has been tested on Candida yeasts and the strategy resulted in a synergistic enhancement of the antifungal action of the azolic chemical product. Indeed, in association with EO, the fluconazole MICs dropped. Thus, the combinatorial use of L. origanoides EO as a chemosensitizer agent should contribute to enhancing the efficiency of conventional antifungal drugs, reducing their negative side effects.

Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity.

BACKGROUND: Caspase Recruitment Domain-containing protein 9 (CARD9) expressed in myeloid cells has been demonstrated to play an antifungal immunity role in protecting against disseminated candidiasis. Hereditary CARD9 ablation leads to fatal disseminated candidiasis. However, the myeloid cell types and molecular mechanisms implicated in CARD9 protecting against disseminated candidiasis remain wholly elusive. METHODS: The role of CARD9 ablation in exacerbating disseminated candidiasis was determined in vivo and in vitro. The molecular mechanism by which CARD9 ablation promotes acute kidney injury in disseminated candidiasis was identified by RNA-sequencing analysis. The expression of mitochondrial proteins and ferroptosis-associated proteins were measured by Quantitative real-time PCR and western blot. RESULTS: CARD9 ablation resulted in a reduced proportion of myeloid-derived suppressor cells (MDSCs) and a substantially lower expression of solute carrier family 7 member 11 (SLC7A11) in the kidneys, which increased susceptibility to acute kidney injury and renal ferroptosis during disseminated Candida tropicalis (C. tropicalis) infection. Moreover, CARD9-deficient MDSCs were susceptible to ferroptosis upon stimulation with C. tropicalis, which was attributed to augmented mitochondrial oxidative phosphorylation (OXPHOS) caused by reduced SLC7A11 expression. Mechanistically, C-type lectin receptors (CLRs)-mediated recognition of C. tropicalis promoted the expression of SLC7A11 which was transcriptionally manipulated by the Syk-PKCδ-CARD9-FosB signaling axis in MDSCs. FosB enhanced SLC7A11 transcription by binding to the promoter of SLC7A11 in MDSCs stimulated with C. tropicalis. Mitochondrial OXPHOS, which was negatively regulated by SLC7A11, was responsible for inducing ferroptosis of MDSCs upon C. tropicalis stimulation. Finally, pharmacological inhibition of mitochondrial OXPHOS or ferroptosis significantly increased the number of MDSCs in the kidneys to augment host antifungal immunity, thereby attenuating ferroptosis and acute kidney injury exacerbated by CARD9 ablation during disseminated candidiasis. CONCLUSIONS: Collectively, our findings show that CARD9 ablation enhances mitochondria-mediated ferroptosis in MDSCs, which negatively regulates antifungal immunity. We also identify mitochondria-mediated ferroptosis in MDSCs as a new molecular mechanism of CARD9 ablation-exacerbated acute kidney injury during disseminated candidiasis, thus targeting mitochondria-mediated ferroptosis is a novel therapeutic strategy for acute kidney injury in disseminated candidiasis.

Genome-wide analysis of in vivo-evolved Candida auris reveals multidrug-resistance mechanisms.

Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.

Patterns recovered in phylogenomic analysis of Candida auris and close relatives implicate broad environmental flexibility in Candida/Clavispora clade yeasts.

Fungal pathogens commonly originate from benign or non-pathogenic strains living in the natural environment. The recently emerged human pathogen, Candida auris, is one example of a fungus believed to have originated in the environment and recently transitioned into a clinical setting. To date, however, there is limited evidence about the origins of this species in the natural environment and when it began associating with humans. One approach to overcome this gap is to reconstruct phylogenetic relationships between (1) strains isolated from clinical and non-clinical environments and (2) between species known to cause disease in humans and benign environmental saprobes. C. auris belongs to the Candida/Clavispora clade, a diverse group of 45 yeast species including human pathogens and environmental saprobes. We present a phylogenomic analysis of the Candida/Clavispora clade aimed at understanding the ecological breadth and evolutionary relationships between an expanded sample of environmentally and clinically isolated yeasts. To build a robust framework for investigating these relationships, we developed a whole-genome sequence dataset of 108 isolates representing 18 species, including four newly sequenced species and 18 environmentally isolated strains. Our phylogeny, based on 619 orthologous genes, shows environmentally isolated species and strains interspersed with clinically isolated counterparts, suggesting that there have been many transitions between humans and the natural environment in this clade. Our findings highlight the breadth of environments these yeasts inhabit and imply that many clinically isolated yeasts in this clade could just as easily live outside the human body in diverse natural environments and vice versa.

Pore-forming peptide C14R exhibits potent antifungal activity against clinical isolates of Candida albicans and Candida auris.

Introduction: Invasive candidiasis is a global public health problem as it poses a significant threat in hospital-settings. The aim of this study was to evaluate C14R, an analog derived from peptide BP100, as a potential antimicrobial peptide against the prevalent opportunistic yeast Candida albicans and the emergent multidrug-resistant yeast Candida auris. Methods: Antifungal susceptibility testing of C14R against 99 C. albicans and 105 C. auris clinical isolates from Colombia, was determined by broth microdilution. Fluconazole was used as a control antifungal. The synergy between C14R and fluconazole was assessed in resistant isolates. Assays against fungal biofilm and growth curves were also carried out. Morphological alterations of yeast cell surface were evaluated by scanning electron microscopy. A permeability assay verified the pore-forming ability of C14R. Results: C. albicans and C. auris isolates had a geometric mean MIC against C14R of 4.42 µg/ml and 5.34 µg/ml, respectively. Notably, none of the isolates of any species exhibited growth at the highest evaluated peptide concentration (200 µg/ml). Synergistic effects were observed when combining the peptide and fluconazole. C14R affects biofilm and growth of C. albicans and C. auris. Cell membrane disruptions were observed in both species after treatment with the peptide. It was confirmed that C14R form pores in C. albicans' membrane. Discussion: C14R has a potent antifungal activity against a large set of clinical isolates of both C. albicans and C. auris, showing its capacity to disrupt Candida membranes. This antifungal activity remains consistent across isolates regardless of their clinical source. Furthermore, the absence of correlation between MICs to C14R and resistance to fluconazole indicates the peptide's potential effectiveness against fluconazole-resistant strains. Our results suggest the potential of C14R, a pore-forming peptide, as a treatment option for fungal infections, such as invasive candidiasis, including fluconazole and amphotericin B -resistant strains.

Early Prediction of Bloodstream Infection with Complete Blood Count Parameters: an Ex-Vivo Human Whole Blood Model.

BACKGROUND: Despite the advanced laboratory technologies available today, blood culture is the gold standard method in the diagnosis of bloodstream infections. Automated blood culture devices give blood culture results for laboratories approximately in 2 - 3 days up to 7 days. Moreover, some microorganisms like nonreproducible bacteria, fungi or viruses cannot be produced in culture. Among all samples taken for blood culture on suspicion of infection approximately 10% are determined as positive whereas the false positive rate due to contamination is 5%. Especially in life-threatening severe conditions such as sepsis early diagnosis and prompt treatment are crucial. Based on this the aim of this study is to investigate complete blood count parameters as potential early markers in Escherichia coli, Staphylococcus aureus and Candida albicans bloodstream infections using an ex vivo whole blood model. METHODS: Blood samples collected from healthy donors (n = 10) were treated with suspensions containing a certain concentration of microorganisms (107 CFU/mL for both E. coli ATCC 25922 and S. aureus ATCC 29213, 106 CFU/mL for C. albicans ATCC 14053). After bacteremia and candidemia were induced, complete blood count parameters were analyzed hourly in the samples until the end of the 4th hour with a Mindray BC-6800 hematology analyzer. Statistical analysis was performed by Tukey-Kramer post-hoc multiple comparison test and statistical significance was accepted as p < 0.05. RESULTS: When platelet derived parameter baseline values were compared to hourly values in E. coli and S. aureus induced whole blood samples, it was found that the decrease in PLT, P-LCC and the increase in IPF% was significant from the first hour whereas the increase in IMG% was found to be significant only from the 3rd hour onward. In the experiments with C. albicans, it was observed that the increase in IPF% and IMG% was significant from the 2nd and 3rd hour onward, respectively. There was no relationship between MPV, P-LCR, and NLR baseline and hourly results in any microorganism induced model. CONCLUSIONS: IPF% can guide clinicians in the early diagnosis and management of treatment of infections caused by S. aureus, E. coli, and C. albicans.

Antifungal activity of ruthenium (II) complex combined with fluconazole against drug-resistant Candida albicans in vitro and its anti-invasive infection in vivo.

With the abuse of antibiotics and azoles, drug-resistant Candida albicans infections have increased sharply and are spreading rapidly, thereby significantly reducing the antifungal efficacy of existing therapeutics. Several patients die of fungal infections every year. Therefore, there is an urgent requirement to develop new drugs. Accordingly, we synthesized a series of polypyridyl ruthenium (II) complexes having the formula [Ru (NN)2 (bpm)] (PF6)2 (N-N = 2,2'-bipyridine) (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3) (bpm = 2,2'-bipyrimidine) and studied their antifungal activities. Ru3 alone had no effect on the drug-resistant strains, but Ru3 combined with fluconazole (FLC) exhibited significant antifungal activity on drug-resistant strains. A high-dose combination of Ru3 and FLC exhibited direct fungicidal activity by promoting the accumulation of reactive oxygen species and damaging the cellular structure of C. albicans. Additionally, the combination of Ru3 and FLC demonstrated potent antifungal efficacy in vivo in a mouse model of invasive candidiasis. Moreover, the combination significantly improved the survival state of mice, restored their immune systems, and reduced renal injury. These findings could provide ideas for the development of ruthenium (II) complexes as novel antifungal agents for drug-resistant microbial stains.

Competitive fungal commensalism mitigates candidiasis pathology.

The mycobiota are a critical part of the gut microbiome, but host-fungal interactions and specific functional contributions of commensal fungi to host fitness remain incompletely understood. Here, we report the identification of a new fungal commensal, Kazachstania heterogenica var. weizmannii, isolated from murine intestines. K. weizmannii exposure prevented Candida albicans colonization and significantly reduced the commensal C. albicans burden in colonized animals. Following immunosuppression of C. albicans colonized mice, competitive fungal commensalism thereby mitigated fatal candidiasis. Metagenome analysis revealed K. heterogenica or K. weizmannii presence among human commensals. Our results reveal competitive fungal commensalism within the intestinal microbiota, independent of bacteria and immune responses, that could bear potential therapeutic value for the management of C. albicans-mediated diseases.

Modeling of intravenous caspofungin administration using an intestine-on-chip reveals altered Candida albicans microcolonies and pathogenicity.

Candida albicans is a commensal yeast of the human intestinal microbiota that, under predisposing conditions, can become pathogenic and cause life-threatening systemic infections (candidiasis). Fungal-host interactions during candidiasis are commonly studied using conventional 2D in vitro models, which have provided critical insights into the pathogenicity. However, microphysiological models with a higher biological complexity may be more suitable to mimic in vivo-like infection processes and antifungal drug efficacy. Therefore, a 3D intestine-on-chip model was used to investigate fungal-host interactions during the onset of invasive candidiasis and evaluate antifungal treatment under clinically relevant conditions. By combining microbiological and image-based analyses we quantified infection processes such as invasiveness and fungal translocation across the epithelial barrier. Additionally, we obtained novel insights into fungal microcolony morphology and association with the tissue. Our results demonstrate that C. albicans microcolonies induce injury to the epithelial tissue by disrupting apical cell-cell contacts and causing inflammation. Caspofungin treatment effectively reduced the fungal biomass and induced substantial alterations in microcolony morphology during infection with a wild-type strain. However, caspofungin showed limited effects after infection with an echinocandin-resistant clinical isolate. Collectively, this organ-on-chip model can be leveraged for in-depth characterization of pathogen-host interactions and alterations due to antimicrobial treatment.

Examination of Oral Candida Infection in Primary Sjögren's Syndrome Patients

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by symptoms such as dry mouth, dry eyes, and other systematic symptoms. Due to the hyposalivation experienced by pSS patients, oral dysbacteriosis often occurs. A common complication of pSS is the oral Candida infection. In this article, the authors describe systematic methods that can effectively diagnose oral Candida infection and identify the Candida strains using saliva, oral mucosal swabs, or mouthwash from pSS patients. The Sabouraud's Dextrose Agar (SDA), hyphal formation assay, potassium hydroxide (KOH) smear test, and calcofluor white (CFW) staining assay are used for the diagnosis of oral Candida infection. A Candida diagnostic agar is used for the identification of Candida strains. Finally, antifungal susceptibility testing is used to determine appropriate antifungal drug treatment. This standardized method can enhance the diagnosis, treatment, and future research of pSS-related oral Candida infections. Early diagnosis, using this method, can also prevent any complications arising due to delay in receiving appropriate treatment.

COVID-19 and oral lesions: 2020-2024 outpatient case series and literature review.

Data on oral lesions of coronavirus disease (COVID-19) are conflicting, and there are few evidence-based data on oral lesions directly caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this case series and literature review is to determine the prevalence of oral lesions associated with COVID-19 in outpatients and identify oral manifestations that are likely associated with COVID-19. We present 15 patients that came for their first specialist examination to the Oral Medicine Outpatient Clinic, Dental Clinic, Split, Croatia between November 2020 and January 2024. Their medical and dental history was taken following CARE guidelines. The prevalence of oral lesions associated with SARS-CoV-2 was 1.42% during the 4-year follow-up period. The most common oral lesions were nonspecific erosions, stomatitis, salivary flow disorders (xerostomia, oligosialia), salivary gland diseases (sialadenitis, chronic sialadenitis), candidiasis, pigmentation, aphthae, burning mouth syndrome, and geographic and fissured tongue. The mean latency period was 25.1 days. The site most commonly affected was the tongue (61.5%). Oral lesions associated with COVID-19 occurred in middle-aged patients, with an equal distribution by sex. They presented in a mild form and did not correlate with the severity of the clinical picture of COVID-19.

Is Candida auris the first multidrug-resistant fungal zoonosis emerging from climate change?

The emergence and evolutionary path of Candida auris poses an intriguing scientific enigma. Its isolation from a pet dog's oral cavity in Kansas, reported by White et al. (T. C. White, B. D. Esquivel, E. M. Rouse Salcido, A. M. Schweiker, et al., mBio 15:e03080-23, 2024, https://doi.org/10.1128/mbio.03080-23), carries significant implications. This discovery intensifies concerns about its hypothetical capacity for zoonotic transmission, particularly considering the dog's extensive human contact and the absence of secondary animal/human cases in both animals and humans. The findings challenge established notions of C. auris transmissibility and underscore the need for further investigation into the transmission dynamics, especially zooanthroponotic pathways. It raises concerns about its adaptability in different hosts and environments, highlighting potential role of environmental and animal reservoirs in its dissemination. Critical points include the evolving thermal tolerance and the genetic divergence in the isolate. This case exemplifies the necessity for an integrated One Health approach, combining human, animal, and environmental health perspectives, to unravel the complexities of C. auris's emergence and behavior.

CARD9 mutations in patients with fungal infections: An update from the last 5 years.

BACKGROUND: Autosomal recessive deficiency in the caspase recruitment domain-containing protein 9 (CARD9) is a congenital immunological condition that leads to susceptibility to mucocutaneous and invasive fungal infections. There is growing incidence of fungal infections in patients with CARD9 deficiency, a phenomenon that is increasingly recognised. OBJECTIVES: This study aimed to assess the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency, based on published papers in the literature until March 2023. METHODS: We swiftly conducted a study to pinpoint every documented instance of fungal infections arising from CARD9 deficiency. We selected case reports from the databases of PubMed, Embase, Scopus and Google Scholar spanning the period from October 2009 to March 2023. RESULTS: We analysed 90 cases of fungal infections and identified 32 mutations in the CARD9 gene. Notably, the homozygous (HMZ) p.Q295X (c.883C > T) mutation was associated with an increased risk of candidiasis. In contrast, the HMZ p.Q289X (c.865C > T) mutation is linked to a higher risk of dermatophytosis. We observed differences in the geographical distribution of these mutations. The primary mutations found in African patients differ from those in Asian patients. Specifically, Asian patients exhibit a broader spectrum of CARD9 mutations than African patients. CONCLUSIONS: The diversity of mutations observed in the 90 cases revealed 32 distinct variations, emphasising the unique genetic alterations in the CARD9 gene associated with specific geographical areas and the corresponding prevalence of fungal infections.

Rapid evolution of an adaptive multicellular morphology of Candida auris during systemic infection.

Candida auris has become a serious threat to public health. The mechanisms of how this fungal pathogen adapts to the mammalian host are poorly understood. Here we report the rapid evolution of an adaptive C. auris multicellular aggregative morphology in the murine host during systemic infection. C. auris aggregative cells accumulate in the brain and exhibit obvious advantages over the single-celled yeast-form cells during systemic infection. Genetic mutations, specifically de novo point mutations in genes associated with cell division or budding processes, underlie the rapid evolution of this aggregative phenotype. Most mutated C. auris genes are associated with the regulation of cell wall integrity, cytokinesis, cytoskeletal properties, and cellular polarization. Moreover, the multicellular aggregates are notably more recalcitrant to the host antimicrobial peptides LL-37 and PACAP relative to the single-celled yeast-form cells. Overall, to survive in the host, C. auris can rapidly evolve a multicellular aggregative morphology via genetic mutations.

Is Silver Addition to Scaffolds Based on Polycaprolactone Blended with Calcium Phosphates Able to Inhibit Candida albicans and Candida auris Adhesion and Biofilm Formation?

Candida spp. periprosthetic joint infections are rare but difficult-to-treat events, with a slow onset, unspecific symptoms or signs, and a significant relapse risk. Treatment with antifungals meets with little success, whereas prosthesis removal improves the outcome. In fact, Candida spp. adhere to orthopedic devices and grow forming biofilms that contribute to the persistence of this infection and relapse, and there is insufficient evidence that the use of antifungals has additional benefits for anti-biofilm activity. To date, studies on the direct antifungal activity of silver against Candida spp. are still scanty. Additionally, polycaprolactone (PCL), either pure or blended with calcium phosphate, could be a good candidate for the design of 3D scaffolds as engineered bone graft substitutes. Thus, the present research aimed to assess the antifungal and anti-biofilm activity of PCL-based constructs by the addition of antimicrobials, for instance, silver, against C. albicans and C. auris. The appearance of an inhibition halo around silver-functionalized PCL scaffolds for both C. albicans and C. auris was revealed, and a significant decrease in both adherent and planktonic yeasts further demonstrated the release of Ag+ from the 3D constructs. Due to the combined antifungal, osteoproliferative, and biodegradable properties, PCL-based 3D scaffolds enriched with silver showed good potential for bone tissue engineering and offer a promising strategy as an ideal anti-adhesive and anti-biofilm tool for the reduction in prosthetic joints of infections caused by Candida spp. by using antimicrobial molecule-targeted delivery.