UNASSIGNED: This manuscript undertakes a systematic examination of the research landscape concerning global Cryptococcus species and their dynamism with the host immune system spanning the past decade. It furnishes a detailed survey of leading knowledge institutions and critical focal points in this area, utilizing bibliometric analysis.
UNASSIGNED: VOSviewer and CiteSpace software platforms were employed to systematically analyze and graphically depict the relevant literature indexed in the WoSCC database over the preceding ten years.
UNASSIGNED: In the interval between October 1, 2013, and October 1, 2023, a corpus of 795 publications was amassed. The primary research institutions involved in this study include Duke University, the University of Minnesota, and the University of Sydney. The leading trio of nations, in terms of publication volume, comprises the United States, China, and Brazil. Among the most prolific authors are Casadevall, Arturo; Wormley, Floyd L., Jr.; and Olszewski, Michal A., with the most highly cited author being Perfect, Jr. The most esteemed journal is Mbio, while Infection and Immunity commands the highest citation frequency, and the Journal of Clinical Microbiology boasts the most significant impact factor. Present research foci encompass the intricate interactions between Cryptococcus pathogenesis and host immunity, alongside immune mechanisms, complications, and immunotherapies.
UNASSIGNED: This represents the first exhaustive scholarly review and bibliometric scrutiny of the evolving landscapes in Cryptococcus research and its interactions with the host immune system. The analyses delineated herein provide insights into prevailing research foci and trajectories, thus furnishing critical directions for subsequent inquiries in this domain.

An amplicon metagenomic approach based on the ITS2 region of fungal rDNA was used to investigate the diversity of fungi associated with mature strawberries collected from a volcanic orchard and open-air market stands. Based on the Kruskal-Wallis test, no statistically significant differences were observed in both non-phylogenetic and phylogenetic alpha diversity indices. According to beta diversity analyses, significant differences in fungal communities were found between groups (orchard vs. market). Taxonomic assignment of amplicon sequence variables (ASVs) revealed 7 phyla and 31 classes. The prevalent fungal phyla were Basidiomycota (29.59-84.58%), Ascomycota (15.33-70.40%), and Fungi-phy-Insertae-sedis (0.45-2.89%). The most predominant classes among the groups were Saccharomycetes in the market group, and Microbotryomycetes and Tremellomycetes in the orchard group. Based on the analysis of microbiome composition (ANCOM), we found that the most differentially fungal genera were Hanseniaspora, Kurtzmaniella, and Phyllozyma. Endophytic yeasts Curvibasidium cygneicollum were prevalent in both groups, while Candida railenensis was detected in fruits originating only from the market. In addition, Rhodotorula graminis (relative abundance varying from 1.7% to 21.18%) and Papiliotrema flavescens (relative abundance varying from 1.58% to 16.55%) were detected in all samples regardless of origin, while Debaryomyces prosopidis was detected in samples from the market only, their relative abundance varying with the sample (from 0.80% to 19.23%). Their role in fruit quality and safety has not been yet documented. Moreover, several clinically related yeasts, such as Meyerozyma guilliermondii and Candida parapsilosis, were detected in samples only from the market. Understanding the variety and makeup of the mycobiome in ripe fruits during the transition from the orchard to the market is crucial for fruit safety after harvest.

Fungal infections caused by Cryptococcus spp. pose a threat to health, especially in immunocompromised individuals. The available arsenal of drugs against cryptococcosis is limited, due to their toxicity and/or lack of accessibility in low-income countries, requiring more therapeutic alternatives. Selective serotonin reuptake inhibitors (SSRIs), through drug repositioning, are a promising alternative to broaden the range of new antifungals against Cryptococcus spp. This study evaluates the antifungal activity of three SSRIs, sertraline, paroxetine, and fluoxetine, against Cryptococcus spp. strains, as well as assesses their possible mechanism of action. Seven strains of Cryptococcus spp. were used. Sensitivity to SSRIs, fluconazole, and itraconazole was evaluated using the broth microdilution assay. The interactions resulting from combinations of SSRIs and azoles were investigated using the checkerboard assay. The possible action mechanism of SSRIs against Cryptococcus spp. was evaluated through flow cytometry assays. The SSRIs exhibited in vitro antifungal activity against Cryptococcus spp. strains, with minimum inhibitory concentrations ranging from 2 to 32 μg/mL, and had synergistic and additive interactions with azoles. The mechanism of action of SSRIs against Cryptococcus spp. involved damage to the mitochondrial membrane and increasing the production of reactive oxygen species, resulting in loss of cellular viability and apoptotic cell death. Fluoxetine also was able to cause significant damage to yeast DNA. These findings demonstrate the in vitro antifungal potential of SSRIs against Cryptococcus spp. strains.

BACKGROUND: Cryptococcosis is an opportunistic systemic mycosis caused by pathogenic encapsulated yeasts of the genus Cryptococcus. The objective of the present study was to evaluate the risk factors associated with death of patients diagnosed with meningitis due to Cryptococcus spp.
METHODS: This retrospective cohort study included patients admitted to the São José Hospital (SJH) with Cryptococcal Meningoencephalitis (CM) who were diagnosed between 2010 and 2018. Data collection was carried out by reviewing the patients\' medical records. Death during hospitalization was considered the primary outcome.
RESULTS: From 2010 to 2018, 21,519 patients were admitted to the HSJ, 124 of whom were hospitalized due to CM. The CM incidence rate was 5.8 cases/103 hospitalizations. We included 112 patients in the study. Male patients were the most affected (82.1%), and the median age was 37 years [IQR: 29-45]. HIV coinfection occurred in 79.4% of the patients. Fever (65.2%) and headache (88.4%) were the most frequent symptoms. Greater cellularity in the CSF was the most related factor to CM in non-HIV individuals (p < 0.05). Death during hospitalization occurred in 28.6% (n = 32) of the patients. The independent risk factors associated with death during the hospitalization were women (p = 0.009), age > 35 years (p = 0.046), focal neurological deficits (p = 0.013), altered mental status (p = 0.018) and HIV infection (p = 0.040). The twelve-month survival was lower in HIV-positive patients (p < 0.05).
CONCLUSIONS: Early diagnosis, optimal treatment, and clinical follow-up strategies, especially in HIV patients, should be prioritized.

BACKGROUND: Cryptococcosis is the most common mycosis of the central nervous system. It may develop in immunocompetent and immunocompromised patients, the latter representing most cases. The most common presentation of the disease is meningitis, whereas intra-axial lesions in the form of cryptococcoma are less frequent with a greater tendency to present in immunocompetent patients. The presentation of pituitary cryptococcoma is exceptional. To the best of the authors\' knowledge, there is only one case published in the medical literature.
METHODS: The authors present the case of a 30-year-old male without a relevant medical history. He was referred to our center with a pituitary mass on magnetic resonance imaging and panhypopituitarism. The patient underwent endonasal endoscopic transsphenoidal tumor resection, and a histopathological diagnosis of pituitary cryptococcoma was made. Medical management included fluconazole and intravenous amphotericin.
CONCLUSIONS: This case underscores the neurosurgical and medical management of an exceptional clinical presentation of pituitary cryptococcoma in an immunocompetent patient. To the best of the authors\' knowledge, there is only one case published in the medical literature. This case provides an invaluable review of the clinical, imaging, and therapeutic considerations regarding this exceptional clinical entity.

Cryptococcus spp. are yeast-type opportunistic fungal pathogens with thick polysaccharide capsules that infect the lungs via airborne routes and frequently cause fatal meningoencephalitis. The cellular immune mechanism plays a central role in controlling cryptococcal infection and is critically regulated by Th1-Th2 immune balance. Pathogens that have invaded the host are recognized by innate immune cells, and appropriate immune responses are initiated. Pathogen-associated molecular patterns (PAMPs) are recognized by macrophages and dendritic cells via pattern recognition receptors (PRRs), which trigger the inflammatory responses as the first line of host defense. Some PRRs, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), are involved in the recognition of cryptococcal components, such as glucuronoxylomannan (GXM), mannoproteins (MPs), and nucleic acids. However, some cryptococcal cell components suppress the host immune response. This review will highlight the cryptococcal components involved in host immune responses. Future research is expected to promote the understanding of the mechanism of host immune response to Cryptococcus, which will lead to the development of new vaccines and therapies for cryptococcal infection.

Chimeric antigen receptors (CARs) redirect T cells to recognize a specific target. CAR components play a pivotal role in antigen specificity, structure stability, expression on cell surface, and induction of cellular activation, which together determine the success of CAR T-cell therapy. CAR products targeting B-cell lymphoma encouraged the development of new CAR applications beyond cancer. For example, our group developed a CAR to specifically target glucuronoxylomannan (GXM) in the capsule of Cryptococcus species, called GXMR-CAR or GXMR-IgG4-28ζ. Cryptococcus are fungi that cause the life-threatening disease cryptococcosis, and GXMR-IgG4-28ζ redirected T cells to target yeast and titan cell forms of Cryptococcus spp. Here, we replaced the IgG4-hinge and CD28-transmembrane domains from GXMR-CAR with a CD8α molecule as the hinge/transmembrane and used CD28 or 4-1BB molecules as co-stimulatory domains, creating GXMR-8-28ζ and GXMR-8-BBζ, respectively. Jurkat cells expressing GXMR-CAR containing CD8α as the hinge/transmembrane improved the CAR expression and induced a tonic signaling. GXMR-8-28ζ and GXMR-8-BBζ induced high levels of IL-2 and up-regulation of CD69 expression in the presence of reference strains of C. neoformans and C. gattii. Moreover, GXMR-8-28ζ and GXMR-8-BBζ showed increased strength in response to incubation with clinical isolates of Cryptococcuss spp., and 4-1BB co-stimulatory domain triggered a more pronounced cellular activation. Dasatinib, a tyrosine kinase inhibitor, attenuated the GXMR-CAR signaling cascade\'s engagement in the presence or absence of its ligand. This study optimized novel second-generation GXMR-CARs containing the CD8-hinge/transmembrane domain that improved CAR expression, antigen recognition, and signal strength in T-cell activation.

Perylene-based compounds, either naturally occurring or synthetic, have shown interesting biological activities. In this study, we report on the broad-spectrum antifungal properties of two lead amphiphilic perylene bisimides, compounds 4 and 5, which were synthesized from perylene-3,4,9,10-tetracarboxylic dianhydride by condensation with spermine and an ammonium salt formation. The antifungal activity was evaluated using a collection of fungal strains and clinical isolates from patients with onychomycosis or sporotrichosis. Both molecules displayed an interesting antifungal profile with MIC values in the range of 2-25 μM, being as active as several reference drugs, even more potent in some particular strains. The ammonium trifluoroacetate salt 5 showed the highest activity with a MIC value of 2.1 μM for all tested Candida spp., two Cryptococcus spp., two Fusarium spp., and one Neoscytalidium spp. strain. Therefore, these amphiphilic molecules with the perylene moiety and cationic ammonium side chains represent important structural features for the development of novel antifungals.

BACKGROUND: Cryptococcal lateral flow antigen assays (CLFAs) have been assessed in comparison to the latex cryptococcal antigen agglutination test but their clinical performance is unknown.
OBJECTIVE: Determine clinical performance of IMMY CLFA (Immuno-Mycologics Inc, Oklahoma) using patients with and without cryptococcosis as the reference standard.
METHODS: One-hundred ninety-seven serum samples from client-owned dogs and cats.
METHODS: Review of medical records of a referral population of dogs and cats that had CLFA performed between 2012 and 2020. Animals were classified as cryptococcosis positive (Cr+) or negative (Cr-) based on clinical information. Clinical diagnosis was used to calculate positive and negative percent agreement of the CLFA.
RESULTS: Twelve specimens (4 canine, 8 feline) were obtained from Cr+ animals and had positive CLFA results. One-hundred eighty-five specimens (139 canine, 46 feline) were collected from Cr- animals. Negative CLFA results were recorded in 129 canine and 44 feline Cr- samples. Positive CLFA results were noted for 10 canine and 2 feline Cr- samples. Positive percent agreement of CLFA was 100% (confidence interval [CI], 39.8%-100% dogs; 63.1%-100% cats). Negative percent agreements were 92.8% (CI, 87.2%-96.5%) for dogs and 95.7% (CI, 85.2%-99.5%) for cats.
CONCLUSIONS: A negative IMMY CLFA result enables reliable exclusion of cryptococcal infection in dogs and cats. By contrast, a positive result must be interpreted cautiously and further testing should be performed to verify a diagnosis of cryptococcosis.

UNASSIGNED: Cryptoccocal meningitis continues to present high incidence among AIDS patients. The treatment of choice is the synergistic combination of flucytosine (5-FC) with amphotericin B deoxycholate (AmBd) or its lipid formulations. However, 5-FC is unavailable in many countries and AmB demands hospitalization. The combination of AmB with the fungistatic fluconazole (FLC) or the use of high FLC daily doses alone became the choice. Nonetheless, sterilization of cerebrospinal fluid is delayed with FLC monotherapy, mainly with high fungal burden. These findings suggest the search for new antifungal compounds, such as liriodenine.
UNASSIGNED: Liriodenine antifungal activity was evaluated by three procedures: determining the minimum inhibitory concentration (MIC) on 30 strains of the Cryptococcus neoformans (C. neoformans) complex and 30 of the Cryptococcus gattii (C. gattii) complex, using EUCAST methodology and amphotericin B deoxycholate as control; performing the time-kill methodology in two strains of the C. neoformans complex and one of the C. gattii complex; and injury to cryptococcal cells, evaluated by transmission electron microscopy (TEM). Liriodenine absorption and safety at 0.75 and 1.50 mg.kg-1 doses were evaluated in BALB/c mice.
UNASSIGNED: Liriodenine MICs ranged from 3.9 to 62.5 μg.mL-1 for both species complexes, with no differences between them. Time-kill methodology confirmed its concentration-dependent fungicidal effect, killing all the strains below the limit of detection (33 CFU.mL-1) at the highest liriodenine concentration (32-fold MIC), with predominant activity during the first 48 hours. Liriodenine induced severe Cryptococcus alterations - cytoplasm with intense rarefaction and/or degradation, injury of organelles, and presence of vacuoles. Liriodenine was better absorbed at lower doses, with no histopathological alterations on the digestive tract.
UNASSIGNED: The fungicidal activity confirmed by time-kill methodology, the intense Cryptococcus injury observed by TEM, the absorption after gavage administration, and the safety at the tested doses indicate that the liriodenine molecule is a promising drug lead for development of anticryptococcal agents.