Search Results (29)

Cryptococcosis, caused by Cryptococcus neoformans, remains a major cause of mortality in immunocompromised patients, with treatment increasingly limited by resistance and toxicity associated with Amphotericin B (Amp B). In this study, methylglyoxal (MG) was evaluated as a virulence-targeted antifungal strategy, with emphasis on its liposomal delivery. MG exhibited superior antifungal activity as compared to Amp B, demonstrating lower MIC values and significantly enhanced inhibition of biofilm formation and laccase activity, key determinants of cryptococcal pathogenicity. Notably, MG showed potent intracellular antifungal activity within macrophages, where C. neoformans persists. Liposomal MG (Lip-MG) markedly reduced macrophage-associated fungal burden under the tested conditions, markedly outperforming both free MG and Amp B formulations. In a leukopenic mouse model of systemic infection, liposomal MG significantly improved survival (up to ~70%) and reduced pulmonary fungal burden as compared to Amp B, which showed limited therapeutic benefit. Importantly, MG-based formulations exhibited a favorable safety profile, with significantly lower nephrotoxicity than Amp B. Collectively, these findings demonstrate that Lip-MG acts through a dual virulence-targeted activity mechanism while effectively eliminating intracellular infection. This dual action, combined with improved safety, highlights MG-based nanotherapy as a promising and translational alternative for the treatment of drug-resistant cryptococcosis. Full article

In this study, we aimed to investigate the clinical characteristics of pulmonary cryptococcosis (PC) patients without acquired immunodeficiency disease (AIDS). In this retrospective study, a total of 101 patients with non-AIDS PC diagnosed at Tangdu Hospital between January 2014 and October 2025 were enrolled. The characteristics of demographic data, underlying diseases, clinical manifestations, laboratory indicators, and clinical outcomes were analyzed. Univariate and multivariate logistic regression analyses were used to identify risk factors for cryptococcal meningitis (CM). Among 101 patients (mean age 53.13 ± 12.31 years; 66.3% male), 56.4% were asymptomatic. Underlying diseases were present in 55.4% (mainly hypertension and diabetes), and CM occurred in 17.8% (18/101). Patients with CM had a higher proportion of underlying diseases (83.3% vs. 49.4%) and lower levels of red blood cells, hemoglobin, total protein, albumin, globulin, and potassium. Multivariate analysis revealed underlying diseases (OR = 7.246, 95% CI: 1.426~55.33), hypoglobulinemia (OR = 0.847, 95% CI: 0.734~0.956), and hypokalemia (OR = 0.177, 95% CI: 0.028~0.778) as independent risk factors for CM. The combined model showed good predictive value (AUC = 0.863). Non-AIDS PC often presents asymptomatically. Patients with underlying diseases, hypoglobulinemia, or hypokalemia are at significantly higher risk for concurrent CM and warrant aggressive central nervous system evaluation. 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

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

Cryptococcosis, an opportunistic fungal infection predominantly caused by Cryptococcus neoformans, is the third most common invasive fungal disease in solid organ transplant recipients. While well-characterized in adult kidney transplant (KT) patients, pediatric data remain sparse. This article compares clinical presentation, immune response, renal involvement, and management strategies of cryptococcosis between adult and pediatric KT recipients. In adults, the disease typically presents as cryptococcal meningitis or pulmonary infection, often complicated by delayed diagnosis and high mortality. In contrast, children frequently exhibit non-specific respiratory symptoms or disseminated disease, reflecting immune immaturity and increased susceptibility to hematogenous spread. Key immunopathological differences include impaired Th1 type responses, macrophage dysfunction, and variable complement activity across age groups. Management involves similar antifungal regimens such as liposomal amphotericin B, flucytosine, and fluconazole, but requires weight-based dosing and careful toxicity monitoring in pediatric patients. Early diagnosis through serum cryptococcal antigen screening, appropriate adjustment of immunosuppressive therapy, and coordinated multidisciplinary care are essential. The findings underscore the need for pediatric specific research and clinical vigilance, emphasizing tailored antifungal dosing and individualized immune management to improve outcomes in this vulnerable population. Full article

Background and Clinical Significance: Since the prevalence of fungal lung infections is increasing, certain agents, such as Cladosporium spp., have emerged as unexpected causes. Cladosporium spp. fungi are ubiquitous in environments such as soil, fruits, and wine corks; they are a part of the normal human skin flora; and they are known respiratory allergens. Case Presentation: A patient with a history of post-COVID-19 syndrome and AIDS presented with lung pathology indicative of an invasive fungal infection. The initial histopathological examination revealed numerous yeast-like cells with narrow-based budding, which led to a mistaken diagnosis of cryptococcosis. However, further detailed examination revealed sparse hyphae in the lung tissue, suggesting a more complex fungal infection. Molecular analyses and sequence BLAST alignment were performed, ultimately identifying the infectious agent as “Cladosporium species novum”, a rare cause of invasive pulmonary cladosporiasis. Conclusions: Invasive pulmonary cladosporiasis is a rare condition, and the morphological features of the fungus alone were insufficient to establish a correct diagnosis. A comprehensive pathohistological and molecular approach with bioinformatics tools is essential for the correct identification of rare and potentially life-threatening fungal pathogens in immunocompromised patients. Full article

Biofilms are structurally organized communities of microorganisms that adhere to a variety of surfaces. These communities produce protective matrices consisting of polymeric polysaccharides, proteins, nucleic acids, and/or lipids that promote shared resistance to various environmental threats, including chemical, antibiotic, and immune insults. While algal and bacterial biofilms are more apparent in the scientific zeitgeist, many fungal pathogens also form biofilms. These surprisingly common biofilms are morphologically distinct from the multicellular molds and mushrooms normally associated with fungi and are instead an assemblage of single-celled organisms. As a collection of yeast and filamentous cells cloaked in an extracellular matrix, fungal biofilms are an extreme threat to public health, especially in conjunction with surgical implants. The encapsulated yeast, Cryptococcus neoformans, is an opportunistic pathogen that causes both pulmonary and disseminated infections, particularly in immunocompromised individuals. However, there is an emerging trend of cryptococcosis among otherwise healthy individuals. C. neoformans forms biofilms in diverse environments, including within human hosts. Notably, biofilm association correlates with increased expression of multiple virulence factors and increased resistance to both host defenses and antifungal treatments. Thus, it is crucial to develop novel strategies to combat fungal biofilms. In this review, we discuss the development and treatment of fungal biofilms, with a particular focus on C. neoformans. Full article

Infections caused by Cryptococcus neoformans and Cryptococcus gattii remain a challenge to our healthcare systems as they are still difficult to treat. In order to improve treatment success, in particular for infections that have disseminated to the central nervous system, a better understanding of the disease is needed, addressing questions like how it evolves from a pulmonary to a brain disease and how novel treatment approaches can be developed and validated. This requires not only clinical research and research on the microorganisms in a laboratory environment but also preclinical models in order to study cryptococci in the host. We provide an overview of available preclinical models, with particular emphasis on models of cryptococcosis in rodents. In order to further improve the characterization of rodent models, in particular the dynamic aspects of disease manifestation, development, and ultimate treatment, preclinical in vivo imaging methods are increasingly used, mainly in research for oncological, neurological, and cardiac diseases. In vivo imaging applications for fungal infections are rather sparse. A second aspect of this review is how research on models of cryptococcosis can benefit from in vivo imaging methods that not only provide information on morphology and tissue structure but also on function, metabolism, and cellular properties in a non-invasive way. Full article

Cryptococcosis in HIV-negative patients can be an opportunistic or endemic disease. There are no published studies on the use of the finger-prick whole blood (point-of-care) cryptococcal antigen lateral flow assay (CrAg LFA) for diagnosing cryptococcosis in HIV-negative patients. We conducted a case series study of HIV-negative patients with cryptococcosis in two centers in São Paulo, Brazil. The objectives were to identify the sensitivity of a finger-prick whole blood CrAg LFA and to describe the main characteristics of this population. We identified 30 HIV-negative patients with cryptococcosis [19 (63%), male; median age, 47 years]. Ten (33%) patients were immunosuppressed, ten (33%) had other comorbidities, and ten (33%) were apparently immunocompetent and without comorbidities. The distribution of the sites of cryptococcosis was as follows: the central nervous system, 90% (n = 27); pulmonary, 43% (n = 13); and other extrapulmonary sites, 40% (n = 12). The sensitivity of the finger-prick whole blood CrAg LFA for the diagnosis of cryptococcosis was 97% (29/30). Among 26 participants with cryptococcal meningitis, the sensitivity of testing cerebrospinal fluid was as follows: CrAg latex agglutination, 77% (20/26); CrAg LFA, 96% (25/26); and culture, 81% (21/26). Culture speciation identified Cryptococcus gattii in 16 (62%) cases, and all had a positive finger-prick whole blood CrAg LFA. This test presented high sensitivity to the diagnosis of cryptococcosis in HIV-negative patients, including those caused by C. gattii. Full article

Fungal infections are an increasingly growing public health concern, and Cryptococcus is one of the most problematic fungal organisms causing substantial mortality and morbidity worldwide. Clinically, this high incidence of cryptococcosis is most commonly seen in immunocompromised patients, especially those who lack an adaptive T cell response, such as HIV/AIDS patients. However, patients with other underlying immunodeficiencies are also at an increased risk for cryptococcosis. The adaptive immune response, in particular the Th1/Th17 T-cell-mediated responses, to pulmonary Cryptococcus infections are required for host protection. Dendritic cells (DCs), encompassing multiple subsets identified to date, are recognized as the major professional antigen-presenting cell (APC) subset essential for the initiation and execution of T-cell immunity. Apart from their prominent role in orchestration of the adaptive arm of the immune defenses, DCs are fully armed cells from the innate immune system capable of the recognition, uptake, and killing of the fungal cells. Thus, DCs serve as a critical point for the endpoint outcomes of either fungal control or unrestrained fungal infection. Multiple studies have shown that DCs are required for anti-cryptococcal defense in the lungs. In addition, the role of DCs in Cryptococcus gattii infections is just starting to be elucidated. C. gattii has recently risen to prominence with multiple outbreaks in the US and Canada, demonstrating increased virulence in non-immunocompromised individuals. C. gattii infection fails to generate an inflammatory immune response or a protective Th1/Th17 T cell response, at least in part, through a lack of proper DC function. Here we summarize the multiple roles of DCs, including subsets of DCs in both mouse and human models, the roles of DCs during cryptococcal infection, and mechanisms by cryptococcal cells to attempt to undermine these host defenses. Full article

Cryptococcosis is a systemic mycosis that causes pneumonia and meningoencephalitis. Strongyloidiasis is a chronic gastrointestinal infection caused by parasites of the genus Strongyloides. Cryptococcosis and strongyloidiasis affect the lungs and are more prevalent in the same world regions, i.e., Africa and tropical countries such as Brazil. It is undeniable that those coincidences may lead to the occurrence of coinfections. However, there are no studies focused on the interaction between Cryptococcus spp. and Strongyloides spp. In this work, we aimed to investigate the interaction between Strongyloides venezuelensis (Sv) and Cryptococcus gattii (Cg) in a murine coinfection model. Murine macrophage exposure to Sv antigens reduced their ability to engulf Cg and produce reactive oxygen species, increasing the ability of fungal growth intracellularly. We then infected mice with both pathogens. Sv infection skewed the host’s response to fungal infection, increasing lethality in a murine coinfection model. In addition to increased NO levels and arginase activity, coinfected mice presented a classic Th2 anti-Sv response: eosinophilia, higher levels of alternate activated macrophages (M2), increased concentrations of CCL24 and IL-4, and lower levels of IL-1β. This milieu favored fungal growth in the lungs with prominent translocation to the brain, increasing the host’s tissue damage. In conclusion, our data shows that primary Sv infection promotes Th2 bias of the pulmonary response to Cg-infection and worsens its pathological outcomes. Full article

Secretory phospholipase B1 (PLB1) and biofilms act as microbial virulence factors and play an important role in pulmonary cryptococcosis. This study aims to formulate the ethanolic extract of propolis-loaded niosomes (Nio-EEP) and evaluate the biological activities occurring during PLB1 production and biofilm formation of Cryptococcus neoformans. Some physicochemical characterizations of niosomes include a mean diameter of 270 nm in a spherical shape, a zeta-potential of −10.54 ± 1.37 mV, and 88.13 ± 0.01% entrapment efficiency. Nio-EEP can release EEP in a sustained manner and retains consistent physicochemical properties for a month. Nio-EEP has the capability to permeate the cellular membranes of C. neoformans, causing a significant decrease in the mRNA expression level of PLB1. Interestingly, biofilm formation, biofilm thickness, and the expression level of biofilm-related genes (UGD1 and UXS1) were also significantly reduced. Pre-treating with Nio-EEP prior to yeast infection reduced the intracellular replication of C. neoformans in alveolar macrophages by 47%. In conclusion, Nio-EEP mediates as an anti-virulence agent to inhibit PLB1 and biofilm production for preventing fungal colonization on lung epithelial cells and also decreases the intracellular replication of phagocytosed cryptococci. This nano-based EEP delivery might be a potential therapeutic strategy in the prophylaxis and treatment of pulmonary cryptococcosis in the future. Full article

Cryptococcosis is one of the most serious opportunistic diseases in patients living with HIV. For this reason, early diagnosis and appropriate treatment are important. Objectives. The aim of the study was to understand the development of patients diagnosed with cryptococcosis by detection of Cryptococcus antigen in serum by lateral flow assay (CrAg LFA) without nervous system involvement and with treatment in accordance with the results. Materials and Methods. A retrospective, longitudinal, analytical study was performed. Seventy patients with cryptococcosis initially diagnosed by serum CrAg LFA without meningeal involvement between January 2019 and April 2022 were analyzed for medical records. The treatment regimen was adapted to the results of blood culture, respiratory material, and pulmonary tomography imaging. Results. Seventy patients were included, 13 had probable pulmonary cryptococcosis, 4 had proven pulmonary cryptococcosis, 3 had fungemia, and 50 had preemptive therapy without microbiological or imaging findings compatible with cryptococcosis. Among the 50 patients with preemptive therapy, none had meningeal involvement or cryptococcosis recurrences to date. Conclusion. Preemptive therapy avoided progression to meningitis in CrAg LFA-positive patients. Preemptive therapy with dose adjustment of fluconazole in patients with the mentioned characteristics was useful despite the use of lower doses than recommended. Full article

The phenotypic plasticity of Cryptococcus neoformans is widely studied and demonstrated in vitro, but its influence on pathogenicity remains unclear. In this study, we investigated the dynamics of cryptococcal cell and transcriptional remodeling during pulmonary infection in a murine model. We showed that in Cryptococcus neoformans, cell size reduction (cell body ≤ 3 µm) is important for initial adaptation during infection. This change was associated with reproductive fitness and tissue invasion. Subsequently, the fungus develops mechanisms aimed at resistance to the host’s immune response, which is determinant for virulence. We investigated the transcriptional changes involved in this cellular remodeling and found an upregulation of transcripts related to ribosome biogenesis at the beginning (6 h) of infection and a later (10 days) upregulation of transcripts involved in the inositol pathway, energy production, and the proteasome. Consistent with a role for the proteasome, we found that its inhibition delayed cell remodeling during infection with the H99 strain. Altogether, these results further our understanding of the infection biology of C. neoformans and provide perspectives to support therapeutic and diagnostic targets for cryptococcosis. Full article

Pulmonary cryptococcosis describes an invasive lung mycosis caused by Cryptococcus neoformans or Cryptococcus gattii complex. It is often a high-consequence disease in both immunocompromised and immunocompetent populations, and may be misdiagnosed as pulmonary malignancy, leading to a delay in therapy. Epidemiology follows that of cryptococcal meningoencephalitis, with C. gattii infection more common in certain geographic regions. Diagnostic tools include histopathology, microscopy and culture, and the detection of cryptococcal polysaccharide antigen or Cryptococcus-derived nucleic acids. All patients with lung cryptococcosis should have a lumbar puncture and cerebral imaging to exclude central nervous system disease. Radiology is key, both as an adjunct to laboratory testing and as the initial means of detection in asymptomatic patients or those with non-specific symptoms. Pulmonary cryptococcomas (single or multiple) may also be associated with disseminated disease and/or cryptococcal meningitis, requiring prolonged treatment regimens. Optimal management for severe disease requires extended induction (amphotericin B and flucytosine) and consolidation therapy (fluconazole) with close clinical monitoring. Susceptibility testing is of value for epidemiology and in regions where relatively high minimum inhibitory concentrations to azoles (particularly fluconazole) have been noted. Novel diagnostic tools and therapeutic agents promise to improve the detection and treatment of cryptococcosis, particularly in low-income settings where the disease burden is high. Full article