Search Results (194)

Cryptococcal meningitis occurs in 62% of persons with HIV-associated meningitis, making Cryptococcus an important cause of meningitis among adults with advanced HIV disease in regions with elevated prevalence of HIV. Despite efforts to advance treatment, the in-hospital death rate of 19% remains unprecedentedly high. Aggregate published clinical trial data evaluating cryptococcosis treatment with survival as the primary endpoint show a significant reduction in the proportion of survivors from diagnosis to 88.5% at 2 weeks of treatment and further to 74% survival at 10 weeks of follow-up (p = 0.001). Disease complications concomitant with unveiling symptoms and reoccurrence of fungal infections, deferment in treatment, and high prevalence of other comorbidities increase the risk of individuals succumbing to cryptococcal meningitis. Among clinical trials of cryptococcal meningitis, the World Health Organization-recommended standard of care was used to randomize participants to the control trial arm. The proportion of participants surviving in the trial was not statistically different between trial randomization arms. In summary, high in-hospital death rates and continued participants’ deterioration post-hospital discharge are challenges for evidence-based new therapies seeking to improve outcomes. Full article

Cryptococcosis is a severe systemic mycosis affecting humans and animals, caused primarily by members of the Cryptococcus neoformans/Cryptococcus gattii species complex. In cats, it is the most common systemic fungal infection and may present with non-specific signs involving the upper respiratory tract, skin, lymph nodes, eyes, or the central nervous system. This study presents two feline cases of cryptococcosis diagnosed by cytological examination and provides an updated literature review. Fine-needle aspiration biopsies were performed in two cats with chronic nasal swelling and submandibular enlargement. Cytological smears stained with hematoxylin and eosin revealed spherical to oval yeast-like organisms with a characteristic thick, non-staining capsule, narrow-based budding, and absence of pseudohyphae, consistent with Cryptococcus spp. Based on cytological findings, both patients were treated with oral itraconazole, resulting in favorable clinical outcomes. A limitation of this study is the lack of mycological culture or molecular confirmation, owing to the owners’ refusal of further diagnostic testing. These cases highlight the diagnostic value of cytology as a rapid tool for differentiating fungal infections from neoplastic processes. Early diagnosis and antifungal therapy are crucial for successful management. From a One Health perspective, feline cryptococcosis may indicate shared environmental exposure risks relevant to both animal and human health. Full article

Cryptococcus neoformans is a major fungal pathogen responsible for life-threatening meningitis, especially in immunocompromised individuals. Although the gut–lung axis is known to regulate immune responses in respiratory infections, its role in cryptococcosis remains unclear. This study aimed to define the dynamic changes in the gut and lung microbiota and their relationship with host immunity during C. neoformans infection. Using a mouse model, we found that pulmonary infection induced significant dysbiosis in both the lung and gut microbiota, marked by decreased beneficial commensals and increased opportunistic pathogens. Integrated analysis showed these microbial shifts were closely associated with distinct immune responses: lung dysbiosis correlated with a strong IL-17-mediated pulmonary inflammatory response, while gut dysbiosis was linked to systemic immune activation in the spleen. Functional metagenomic prediction further revealed widespread disruption in microbial metabolic pathways, including energy metabolism and biosynthesis, in both sites. Importantly, a positive correlation was observed between lung and gut dysbiosis, indicating an interconnected gut–lung axis during cryptococcosis. These findings demonstrate that C. neoformans infection causes coordinated disruptions in microbiota and immunity across the gut–lung axis, underscoring the microbiome as a critical modulator of host response and suggesting potential avenues for microbiome-targeted therapies. Full article

Genetic variation underlies the capacity of populations to adapt, yet what drives how this variation is generated and maintained in natural populations remains poorly understood. Fundamental processes such as mutation, ploidy, and recombination are known to shape genetic variation and adaptive potential but are typically studied in isolation and under controlled laboratory conditions. How these processes act together under varying environmental conditions to structure genetic variation across complex natural populations remains unresolved. In yeasts, these processes are dependent on reproductive mode, ploidy shifts, and environmental stressors, which jointly shape genomic stability and adaptive potential. Here, we review our current knowledge on the roles of mutation, ploidy, and recombination in adaptation in the model yeasts Saccharomyces cerevisiae and the human pathogenic Cryptococcus. We highlight heterogeneity in mutation rates, recombination, and ploidy states across strains, environments, and populations, challenging the assumption that these parameters are uniform. We argue that fluctuating environments, increasingly driven by climate change, are likely to intensify interactions among these processes to impact evolution in ways that remain difficult to predict. Integrating population genomics with ecologically realistic frameworks will be essential for understanding natural evolutionary dynamics and anticipating fungal adaptation and disease emergence. Full article

Since 1997, a laboratory-based survey on cryptococcosis has been conducted in Colombia. We present the results for the period 2017–2024. A total of 891 surveys were received. The overall incidence was 0.22 cases per 100,000 people. Among those living with HIV, the incidence was 38, and among HIV-negative people, it was 0.08. Cryptococcosis demonstrated a higher prevalence among men than women (3.2:1). Among patients living with Human Immunodeficiency Virus (HIV), the condition primarily affected younger adults (26–40 years). In contrast, among HIV-negative people, it was mostly observed in older adults (≥60 years). HIV infection was the most significant risk factor (63%), but another cause of immunosuppression was identified in 21.2% cases. Neurocryptococcosis was the most common form of presentation (62.2%), followed by disseminated cryptococcosis (31.1%). The diagnosis was confirmed by culture in 99.4% of patients; the most important sample was cerebrospinal fluid (67.3%), followed by blood (35.4%). Cryptococcus neoformans was identified in 93.1% of cases, and Cryptococcus gatti in 6.9%. Predominant molecular patterns were VNI (92.4%) and VGII (45.3%). The epidemiology of cryptococcosis in Colombia is changing, with a progressive decrease in HIV coinfection and an increase in other immunosuppressive conditions in older people. This study highlights the importance of cryptococcosis in Colombia and the need to report it in order to improve knowledge and thereby promote the quality of diagnosis and the opportunity for more effective treatment. Full article

Cryptococcus neoformans is a pathogenic yeast and the leading cause of cryptococcosis in humans. The calcium-calcineurin signaling pathway plays a central role in stress adaptation and virulence. To identify the uncharacterized regulators of fungal adaptation, we utilized an integrative systems biology approach, combining differential gene expression and network analysis using transcriptomic data from three key components of the calcium-calcineurin pathway (Cna1, Crz1, and Pmc1). Our workflow identified the CNAG_00522 gene product, which we designated tricalbin 1 (TCB1) due to its conserved calcium and lipid-binding C2 domains. TCB1 expression was found to be regulated by both Cna1 and Pmc1. Network analyses positioned Tcb1 as a bottleneck linking general stress response and cellular processes. Further molecular characterization confirmed that TCB1 expression is temperature and calcium-responsive. Functional studies of the tcb1Δ mutant revealed an enlarged capsule, increased GXM shedding, and enhanced viability under host-mimicking conditions. However, phenotypic screening demonstrated that the tcb1Δ mutant does not display sensitivity to cell wall or osmotic stressors, and TCB1 deletion did not attenuate virulence in the Tenebrio larval model. These findings suggest that TCB1 functions as a specialized regulator of fungal growth at 37 °C, capsule size, and GXM shedding. This study validates our integrative approach for guiding the identification of these complex regulators. Full article

Feline cryptococcosis is a common systemic mycosis that typically begins in the nasal cavity and can extend to the eyes, skin, and CNS. Objective monitoring during therapy remains limited. This study aimed to test whether serial serum cryptococcal antigen titers (CALAS) and a simple six-domain clinical score can track response, and to describe clinicopathologic trends during amphotericin B and fluconazole treatment. We retrospectively reviewed cases from 2014 to 2023 and analyzed a single-center cohort of 35 cats. Management used amphotericin B plus fluconazole for ~3–4 months, then fluconazole maintenance. Monthly assessments included CALAS (log₂), the clinical score (0–18), and routine hematology/biochemistry; mixed-effects models tested change over time. CALAS fell (mean log₂ 12.00 to 6.79), total leukocytes decreased (16.85 × 10⁹/L to 10.90 × 10⁹/L) with a similar neutrophil decline, alanine aminotransferase remained stable, and blood urea nitrogen/creatinine increased in some cats. The clinical score improved from 3.83 to 0.68. Seven cats developed azotemia during amphotericin B; the drug was stopped, renal values normalized in three, and four remained azotemic at the last follow-up. These findings support the use of CALAS and a simple score as practical monitoring tools and underscore the need for routine renal surveillance. Full article

Central nervous system (CNS) cryptococcosis caused by Cryptococcus neoformans is a severe opportunistic infection that primarily affects individuals with impaired cellular immunity. Although the classic presentation includes headache, fever, and meningeal signs, chronically immunosuppressed patients may develop atypical neuropsychiatric manifestations, leading to diagnostic delays. We report the case of a 53-year-old man with rheumatoid arthritis (RA) receiving long-term prednisolone and etanercept therapy, who presented with a 7-day history of depressive mood, anhedonia, social withdrawal, irritability, and progressive confusion. Neurological examination revealed disorientation without focal deficits. Brain imaging showed only mild cortical atrophy, and cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis, low glucose, and elevated protein levels. Multiplex PCR (FilmArray^®) of CSF identified Cryptococcus neoformans, CSF positive to C. neoformans. The patient was treated with liposomal amphotericin B followed by fluconazole, resulting in gradual improvement of both neurological and psychiatric symptoms. This case highlights an unusual presentation of CNS cryptococcosis in a non-HIV immunosuppressed patient with RA, emphasizing that acute psychiatric or cognitive changes can be the predominant manifestation. Clinicians should consider fungal infections in the differential diagnosis of acute neuropsychiatric symptoms in patients receiving chronic corticosteroid and biologic therapy. Early recognition and molecular diagnosis can facilitate timely antifungal treatment, potentially improving prognosis and reducing morbidity associated with delayed therapy. This report underscores the importance of awareness of atypical presentations of opportunistic infections in immunosuppressed populations. Full article

Infections with strains of the Cryptococcus neoformans species complex are responsible for over 100,000 deaths per year, predominantly due to meningitis in immunocompromised individuals. Despite much research, there are no licensed fungal vaccines available. Most experimental cryptococcal vaccine formulations have been tested in preclinical models using laboratory strains of C. neoformans, particularly H99 and KN99. However, to be effective, vaccines need to protect against the wide variety of cryptococcal isolates found worldwide, particularly in regions that have the highest burden of infections. Therefore, we explored vaccine-mediated protection of BALB/c mice against experimental cryptococcosis due to six C. neoformans strains originally isolated from patients with cryptococcal meningitis in Vietnam, Uganda, and Botswana. Two vaccines were tested: a live-attenuated C. neoformans vaccine lacking three chitin deacetylase genes, and a quadrivalent subunit protein vaccine adjuvanted with Cationic Adjuvant Formulation 01. When compared to unvaccinated mice, both vaccines provided significant protection against all six clinical strains. However, the degree of protection varied as a function of vaccine formulation and clinical strain. Lung leukocytes from vaccinated and infected mice had significantly increased antigen-stimulated interferon-gamma production compared with infected but unvaccinated mice. Thus, although the degree of protection varied, two cryptococcal vaccines significantly protected mice against experimental infection with cryptococcal strains representative of regions of the world that account for the majority of cryptococcal meningitis cases found globally. These data provide preclinical support for trialing vaccines in persons at high risk for developing cryptococcosis. Full article

CGSC is a pathogenic basidiomycetous yeast of increasing public health concern due to its ability to cause life-threatening infections in both immunocompromised and immunocompetent individuals. C. gattii species complex (CGSC) is acquired via environmental exposure, particularly through the inhalation of spores from trees, soil, and decaying wood. Infections often manifest in the pulmonary or central nervous system, both of which are associated with high morbidity and mortality. Compounding this threat is the pathogen’s expanding geographic range, facilitated in part by climate change, and the limited effectiveness of antifungal therapies that are available. Genetic diversity among molecular types (VGI–VGVI) contributes to variable antifungal susceptibility, further complicating treatment. Knowledge of risk factors for the CGSC are limited. Despite its rising global footprint and potential for severe diseases, CGSC remains underreported, with surveillance gaps even in endemic regions. This review highlights the pathogen’s epidemiology, risk factors, clinical impact, and therapeutic challenges, arguing for changes in policy that would increase reporting efforts worldwide. Improved surveillance, public health education, and antifungal research are critical to curbing the growing burden of CGSC infections worldwide. Full article

Pulmonary cryptococcosis is an invasive fungal infection usually linked to severe immunosuppression, particularly HIV/AIDS, but is increasingly reported in immunocompetent hosts, including those with uncontrolled diabetes mellitus (DM). We describe a 51-year-old woman with poorly controlled type 2 DM and no other immunosuppressive conditions who developed pulmonary cryptococcosis. Diagnosis was made by microscopy, India ink, cryptococcal antigen lateral flow assay (CrAg LFA), and ITS sequencing; culture was negative. Despite treatment with deoxycholate amphotericin B and fluconazole, the patient died 36 days after admission. A systematic literature review (2000–2025) identified 40 cases of pulmonary cryptococcosis, with 17.5% occurring in patients whose only comorbidity was DM. Cryptococcus neoformans was the most frequent species. Non-culture-based methods, especially CrAg detection, were widely used, underscoring their value for rapid and sensitive diagnosis. Pulmonary cryptococcosis should be considered in diabetic patients even without classical immunosuppression. Broader use of non-culture-based diagnostic tools may enable earlier intervention, which is particularly relevant in resource-limited settings such as Honduras. Full article

Background: Cryptococcosis, a systemic mycosis, remains a neglected disease in Brazil due to the absence of systematic national surveillance. This study developed an interactive dashboard to analyze cryptococcosis-related deaths (2000–2022) and forecast trends through regional ARIMA modeling. Methodology: The Cross-Industry Standard Process for Data Mining framework was employed to extract mortality data from the Brazilian Mortality Information System, utilizing the microdatasus package in R Studio software, with R version 3.4.0. The records were then filtered using the International Classification of Diseases, Tenth Revision codes (B45 series) to identify primary and associated causes of death. After data extraction, a series of data preprocessing steps was implemented, including deduplication, variable recoding, and the management of missing values. The Shiny framework was employed to construct an interactive dashboard, incorporating Plotly and DT packages, with time-series visualizations, demographic variables, and multilingual support (Portuguese/English). Results: Among 12,308 deaths (2227 primary; 10,081 associated causes), most occurred in males aged 21–60 years. Data completeness was high for age/residence (100%) but lower for education (82%). The dashboard enables dynamic exploration of trends, demographic patterns, and open-data downloads. Regional ARIMA models revealed heterogeneous forecasts, with the Southeast projecting a decline (193 deaths in 2025; 95% CI: 146–240) and the South showing stability (141 deaths; 95% CI: 109–173). Conclusions: This tool bridges a critical gap in cryptococcosis surveillance, enabling dynamic mortality trend analysis, identification of high-risk demographics, and regional forecasting to guide public health resource allocation. While the absence of HIV serostatus data limits etiological analysis, the dashboard’s open-source framework supports adaptation for other neglected diseases. Full article

Leishmania spp. are obligatory intracellular parasites that primarily infect macrophages. The macrophage immune response plays a pivotal role in determining the control or progression of infection. “M1-like” macrophages mediate parasite clearance through the production of nitric oxide, pro-inflammatory cytokines, and reactive oxygen species, whereas “M2-like” macrophages contribute to infection progression by exerting anti-inflammatory effects. The capsular polysaccharides Glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal) from Cryptococcus neoformans are capable of immunomodulating the macrophage response. GXM exhibits immunoregulatory activity, whereas GXMGal induces a pro-inflammatory response. Although the activity of these polysaccharides has been studied in cryptococcosis, their immunomodulatory potential in other infectious models remains largely unexplored. Here, we investigated the effects of GXM and GXMGal on Leishmania major infection in murine peritoneal macrophages. Murine peritoneal macrophages were infected with L. major and, 24 h post-infection, treated with 50 μg of either GXM or GXMGal. Our data revealed that GXM treatment enhanced L. major infection, while GXMGal treatment had no significant effect on the parasitic load in infected macrophages. Full article

Cryptococcosis, caused by the Cryptococcus neoformans and Cryptococcus gattii species complexes (pathogenic Cryptococcus spp.), is an environmentally acquired mycosis of One Health relevance. This study integrates a PRISMA-compliant systematic review (2000–2025) of Portuguese animal, human, and environmental reports with a 13-year retrospective dataset of laboratory-confirmed veterinary cryptococcosis cases (2013–2025). Clinical specimens were cultured and identified by MALDI-TOF mass spectrometry, and associations were assessed using χ² and Fisher’s exact tests. Of 1059 submissions, 48 (4.5%) were culture-positive: 6.8% of canine, 5.3% of feline samples, and 4.0% of avian samples, with no detections in other vertebrate groups (p = 0.705). Cryptococcus neoformans predominated in carnivores (73.7%), while Papiliotrema laurentii (formerly Cryptococcus laurentii) was most frequent in birds (86.2%). Infection was not associated with sex or age. Seasonality was evident, with a July peak and summer predominance (p = 0.010). Most cases were from the Centre region (62.5%), with significant regional variation of Cryptococcus spp. distribution (p < 0.001). The systematic review confirmed autochthonous C. gattii complex disease and widespread C. neoformans contamination in pigeon guano and arboreal niches. These findings demonstrate a compartmentalised eco-epidemiology, reinforcing the need for integrated molecular typing, antifungal susceptibility testing, and coordinated human–animal–environment surveillance to inform targeted prevention and control strategies in Portugal. Full article

Background/Objectives: Cryptococcus gattii presents a significant threat to healthy individuals. Titan cell formation, a key virulence factor, is influenced by the nutritional environment and plays a critical role in immune evasion and stress resistance. This study investigates the molecular and biophysical changes in titanized C. gattii cells grown in nutrient-rich Neurobasal™ medium, a potent inducer of titan cells. Methods: An integrative approach was used, combining scanning electron microscopy, optical tweezers, fluorescence microscopy, and physicochemical methods to analyze C. gattii cells grown in Neurobasal™ medium and minimal media. Results: Cells grown in Neurobasal™ medium exhibited significant differences compared to those grown in minimal media. These included a thicker and more defined polysaccharide capsule, enhanced capsule elasticity, and the secretion of more elastic polysaccharides. Furthermore, cells grown in the enriched medium showed reduced susceptibility to antifungals and delayed mortality in infection models. Conclusions: C. gattii adapts to nutritional cues by forming titan cells, thereby enhancing its pathogenicity. Targeting nutritional sensing pathways may offer novel therapeutic strategies against cryptococcal infections. Full article