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Journal articles on the topic 'Cryptococcus neoformans capsular antigen'

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Published: 3 June 2025

Last updated: 13 July 2025

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De Jesus, Magdia, André Moraes Nicola, Marcio L. Rodrigues, Guilhem Janbon, and Arturo Casadevall. "Capsular Localization of the Cryptococcus neoformans Polysaccharide Component Galactoxylomannan." Eukaryotic Cell 8, no. 1 (2008): 96–103. http://dx.doi.org/10.1128/ec.00331-08.

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ABSTRACT Cryptococcus neoformans capsular polysaccharide is composed of at least two components, glucuronoxylomannan (GXM) and galactoxylomannans (GalXM). Although GXM has been extensively studied, little is known about the location of GalXM in the C. neoformans capsule, in part because there are no serological reagents specific to this antigen. To circumvent the poor immunogenicity of GalXM, this antigen was conjugated to protective antigen from Bacillus anthracis as a protein carrier. The resulting conjugate elicited antibodies that reacted with GalXM in mice and yielded an immune serum that proved useful for studying GalXM in the polysaccharide capsule. In acapsular cells, immune serum localized GalXM to the cell wall. In capsulated cells, immune serum localized GalXM to discrete pockets near the capsule edge. GalXM was abundant on the nascent capsules of budding daughter cells. The constituent sugars of GalXM were found in vesicle fractions consistent with vesicular transport for this polysaccharide. In addition, we generated a single-chain fraction variable fragment antibody with specificity to oxidized carbohydrates that also produced punctate immunofluorescence on encapsulated cells that partially colocalized with GalXM. The results are interpreted to mean that GalXM is a transient component of the polysaccharide capsule of mature cells during the process of secretion. Hence, the function of GalXM appears to be more consistent with that of an exopolysaccharide than a structural component of the cryptococcal capsule.

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Birkhead, Monica, Serisha D. Naicker, Nozuko P. Blasich, et al. "Cryptococcus neoformans: Diagnostic Dilemmas, Electron Microscopy and Capsular Variants." Tropical Medicine and Infectious Disease 4, no. 1 (2018): 1. http://dx.doi.org/10.3390/tropicalmed4010001.

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Two cases of cryptococcal meningitis went undetected by a cryptococcal antigen (CrAg) lateral flow assay on blood in a reflex CrAg screen-and-treat programme in South Africa, although Cryptococcus neoformans was identified by culturing the cerebrospinal fluid specimens. Further investigations into these discordant diagnostic results included multilocus sequence typing (which showed no mutations in the CAP59 gene) and transmission electron microscopy using a capsule-staining protocol (which revealed a >50% reduction in capsular material in both cases, relative to a control culture). A multi-disciplinary approach for resolving discordant diagnostic test results is recommended.

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Negroni, R., C. Cendoya, A. I. Arechavala, et al. "Detection of Cryptococcus neoformans capsular polysaccharide antigen in asymptomatic HIV-infected patients." Revista do Instituto de Medicina Tropical de São Paulo 37, no. 5 (1995): 385–89. http://dx.doi.org/10.1590/s0036-46651995000500002.

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Serum samples from 242 HIV-positive persons were studied for the detection of capsular polysaccha-ride antigen of Cryptococcus neoformans; 193 of these patients presented less than 300 CD4+ cells/µl of blood and 49 patients had more than 300 CD4+ cells/µl. None of them had symptoms or signs characteristic of cryptococcosis. The capsular antigen of C. neofarmans was detected by latex agglutination technique with pronase pre-treatment (IMMY, Crypto-Latex Antigen Detection System, Immunomycologics Inc., OK, USA); in 61% of the samples, ELISA technique was also used (Premier, Cryptococcal Antigen, Meridian Diagnostic Inc., Cincinatti, Oh, USA). The comparative study of both methods showed that the results obtained were similar in 96.9% of the cases. The capsular antigen was detected in 13 out of 193 (6.7%) patients with less than 300 CD4+ cells/µl. Cryptococcosis was confirmed mycologically in 3 of these 13 cases (23%) by the isolation of C. neoformans in CSF or blood cultures. Three patients, who had presented negative results of both tests for capsular antigen, suffered disseminated cryptococcosis 4 to 8 months later. The predictive diagnostic value of capsular antigen detection of C. neoformans seems tobe low and we believe that it should not be done routinely in asymptomatic HIV-positive persons.

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Martinez, Luis R., Dariush Moussai, and Arturo Casadevall. "Antibody to Cryptococcus neoformans Glucuronoxylomannan Inhibits the Release of Capsular Antigen." Infection and Immunity 72, no. 6 (2004): 3674–79. http://dx.doi.org/10.1128/iai.72.6.3674-3679.2004.

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ABSTRACT Cryptococcus neoformans releases capsular polysaccharide in the supernatant of liquid cultures and in tissues. Significantly less glucuronoxylomannan (GXM) was released by C. neoformans in the presence of capsule-binding monoclonal antibody (MAb). MAb-mediated inhibition of GXM release may be another mechanism by which humoral immunity can mediate protection against this pathogen.

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Rohatgi, Soma, and Liise-anne Pirofski. "Molecular characterization of antigen-specific B1 and B2 B-cells populations in Cryptococcus neoformans infection in mice (43.1)." Journal of Immunology 188, no. 1_Supplement (2012): 43.1. http://dx.doi.org/10.4049/jimmunol.188.supp.43.1.

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Abstract We examined B1 and B2 B-cell repertoires in Cryptococcus neoformans infection in mice. Flow-cytometry based antigen-specific staining for B-cell populations generated in response to pulmonary infection was performed using labeled un-encapsulated and encapsulated C. neoformans strains. FACS sorting and single-cell nested PCR was employed to characterize the IgH repertoire. An increase in total peritoneal B1a, B1b and B2 cell numbers was observed as early as day 3 post-infection. Frequencies of both acapsular and capsular antigen-specific cells were increased in the B1a subpopulation (18%, 5%) in infected compared to naïve mice (11%, 2%). The heavy chains of antigen-specific B2 and B1b cells recognizing acapsular and capsular cryptococcus belonged predominantly to the VH1 family. Interestingly, increased VH11 (22%) and VH12 (33%) usage was observed in antigen-specific B1a cells recognizing acapsular and encapsulated cryptococcus, respectively, compared to the conventional B1a population. Although all acapsular (VH11+) and capsular (VH12+) B1a cells used the same VH11.2.53 and VH12.1.78 genes, 60% and 80% rearrangements were unique, respectively. VH genes in both cases were essentially germline, however 40% of acapsular specific B1a cells had 4 or more N-nucleotide additions compared to capsular specific B1a cells (20%). These results indicate that naturally occurring phosphatidyl choline reactive B1a cells have broad specificities and can bind to encapsulated cryptococcus.

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Martinez, Luis R., and Arturo Casadevall. "Specific Antibody Can Prevent Fungal Biofilm Formation and This Effect Correlates with Protective Efficacy." Infection and Immunity 73, no. 10 (2005): 6350–62. http://dx.doi.org/10.1128/iai.73.10.6350-6362.2005.

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ABSTRACT One of the most troublesome medical problems today is infection of prosthetic devices with organisms that form polysaccharide biofilms. This combined with increasing antimicrobial drug resistance is making many infectious diseases incurable. Cryptococcus neoformans is a human-pathogenic fungus that has a polysaccharide capsule and can form biofilms in prosthetic medical devices. We developed a system to study cryptococcal biofilm formation in vitro and studied the effect of antibody to the C. neoformans capsular polysaccharide on this process. C. neoformans biofilm formation was dependent on the presence of a polysaccharide capsule and correlated with the ability of capsular polysaccharide to bind the polystyrene solid support. Protective antibodies prevented biofilm formation whereas nonprotective antibodies were not effective. The mechanism of antibody action involved interference with capsular polysaccharide release from the fungal cell. In contrast, lactoferrin, an effector molecule of innate immune mechanisms, was unable to prevent fungal biofilm formation despite its efficacy against bacterial biofilms. Our results suggest a new role of adaptive humoral immunity whereby some antibodies can inhibit biofilm formation by encapsulated organisms. Vaccines that elicit antibody responses to capsular antigens and/or passive transfer of antibodies to microbial polysaccharides may be useful in preventing biofilm formation.

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Swinne, D., and C. De Vroey. "Detection of circulating capsular polysaccharide antigen from Cryptococcus neoformans." Journal of Clinical Microbiology 30, no. 9 (1992): 2521. http://dx.doi.org/10.1128/jcm.30.9.2521-.1992.

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Widjaja, Sajuni, Erwin Astha Triyono, Arthur Pohan Kawilarang, and Abu Rohiman. "CRYPTOCOCCAL ANTIGENEMIA IN HIV/AIDS PATIENTS USING LATERAL FLOW IMMUNOASSAY DETECTION AT Dr. SOETOMO GENERAL HOSPITAL SURABAYA." Indonesian Journal of Tropical and Infectious Disease 7, no. 1 (2018): 11. http://dx.doi.org/10.20473/ijtid.v7i1.6311.

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Cryptococcus infection in HIV / AIDS patients results in cryptococcal meningitis, a major cause of subacute meningitis with 100% mortality if not receiving appropriate antifungal therapy. An examination of cryptococcal antigen will provide risk information for patients who will experience cryptococcal meningitis. Better diagnosis in asymptomatic and symptomatic phases of cryptococcosis are key components to reduce morbidity and mortality. This study aims to determine the proportion of cryptococcal antigenemia in HIV / AIDS patients treated at Intermediate Treatment-Infectious Diseases Unit of Dr. Soetomo General Hospital Surabaya. Cryptococcal antigenemia was examined in HIV / AIDS patients with suspected Cryptococcus infection and CD4+ T cell lymphocyte count <200 cell /μl. The examination used a lateral flow assay diagnostic tool, a simple FDA(Food and Drug Administration)-approved immunochromatographic test system for detection of capsular polysccharide antigens of Cryptococcus species complex (Cryptococcus neoformans and Cryptococcus gattii) in blood. This test meets all of the World Health Organization ASSURED criteria (affordable, sensitive, specific, user friendly, rapid/robust, equipment-free, and delivered). Sensitivity and specifiticy of this method from serum are both 100%. There were 3 positive cryptococcal antigenemia from 41 serum HIV / AIDS patients with suspected cryptococcus infection at Intermediate Treatment- Infectious Diseases Unit of Dr. Soetomo General Hospital Surabaya. All of these patients were male aged over 36 years, had CD4+ T cell lymphocytes <100 cell /μl and had never received antiretroviral therapy before. The proportion of cryptococcal antigenemia in HIV / AIDS patients with suspected Cryptococcus infection at Intermediate Treatment-Infectious Diseases Unit of Dr. Soetomo General Hospital Surabaya was 7.32%.

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Retini, Cinzia, Anna Vecchiarelli, Claudia Monari, Francesco Bistoni, and Thomas R. Kozel. "Encapsulation of Cryptococcus neoformans with Glucuronoxylomannan Inhibits the Antigen-Presenting Capacity of Monocytes." Infection and Immunity 66, no. 2 (1998): 664–69. http://dx.doi.org/10.1128/iai.66.2.664-669.1998.

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ABSTRACT This report examines the effect of the major capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), on the antigen-presenting capability of human monocytes treated with acapsular cells of C. neoformans. We found that pretreatment of acapsular cryptococci with GXM downregulates, in a dose-dependent manner, the antigen-presenting capacity of monocytes, leading to reduced proliferative T-lymphocyte responses. Similar levels of suppression occurred when monocytes were exposed to encapsulated cryptococci or acapsular cryptococci that were pretreated with GXM. The magnitude of the T-cell response correlated with the ability of monocytes to ingest the yeast. Supernatant fluids from cocultures of monocytes and T cells cultured with encapsulated cryptococci contained higher levels of interleukin-10 (IL-10) than supernatant fluids of cells with acapsular cryptococci. Addition of anti-IL-10 monoclonal antibodies to the incubation medium of monocytes and T cells cultured with encapsulated cryptococci restored proliferative T-cell responses to levels observed during culture with acapsular cryptococci. Finally, treatment of monocytes with encapsulated cryptococci or GXM-treated acapsular cryptococci suppressed expression of class II major histocompatibility complex (MHC) molecules in a manner consistent with previous reports of IL-10-mediated suppression of class II MHC molecules and suppression of proliferative T-cell responses. These results suggest a link between GXM encapsulation, increased IL-10 synthesis by monocytes, decreased expression of class II MHC molecules on monocytes, and reduced proliferative T-cell responses.

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Dornelles, Gustavo, Glauber R. de S. Araújo, Marcus Rodrigues, Vinicius Alves, Rodrigo Almeida-Paes, and Susana Frases. "Comparative Analysis of Capsular and Secreted Polysaccharides Produced by Rhodotorula mucilaginosa and Cryptococcus neoformans." Journal of Fungi 9, no. 11 (2023): 1124. http://dx.doi.org/10.3390/jof9111124.

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Fungal infections are a global public health challenge, especially among immunocompromised patients. Basidiomycetous yeasts, such as Rhodotorula mucilaginosa, have emerged as opportunistic pathogens, but have received less attention than Cryptococcus neoformans. This study aimed to characterize the polysaccharides of R. mucilaginosa and compare them with those of C. neoformans, analyzing their clinical implications. Comprehensive physicochemical, mechanical, and ultrastructural analyses of polysaccharides from both species were performed, revealing correlations with virulence and pathogenicity. R. mucilaginosa cells are surrounded by a capsule smaller than that produced by C. neoformans, but with similar polysaccharides. Those polysaccharides are also secreted by R. mucilaginosa. Cross-reactivity with R. mucilaginosa was observed in a diagnostic C. neoformans antigen test, using both in vitro and in vivo samples, highlighting the need for more reliable tests. Some R. mucilaginosa strains exhibited virulence comparable to that of C. neoformans in an invertebrate experimental model (Tenebrio molitor). This study contributes to a deeper understanding of yeast pathogenicity and virulence, highlighting the need for more accurate diagnostic tests to improve the differential diagnosis of infections caused by basidiomycetous yeasts.

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Pietrella, Donatella, Stefano Perito, Francesco Bistoni, and Anna Vecchiarelli. "Cytotoxic T Lymphocyte Antigen Costimulation Influences T-Cell Activation in Response to Cryptococcus neoformans." Infection and Immunity 69, no. 3 (2001): 1508–14. http://dx.doi.org/10.1128/iai.69.3.1508-1514.2001.

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ABSTRACT The kinetics of cytotoxic T lymphocyte antigen 4 (CTLA-4) expression on T cells responding to Cryptococcus neoformansand its role in regulating the T-cell response were examined. Using peripheral blood mononuclear cells stimulated with encapsulated or acapsular C. neoformans we showed that (i) the encapsulated strain augmented CTLA-4 expression on the T-cell surface while the acapsular strain was a weaker modulator, (ii) CTLA-4 molecules were rapidly up-regulated after the addition of encapsulated C. neoformans, (iii) CTLA-4 was up-regulated predominantly in CD4+ T cells responding to C. neoformans, and (iv) blockage of CTLA-4 with (Fab′)2 of monoclonal antibody to CTLA-4 induced T-cell proliferation that paralleled the enhancement of interleukin-2 and gamma interferon production. These results suggest that capsular material, the major virulence factor of C. neoformans, promotes synthesis and expression of CTLA-4 molecules predominantly in CD4+ T cells. CTLA-4-mediated deactivation is due not to lack of costimulation but to specific recognition of CTLA-4 for B7 molecules. This appears to be a new mechanism by whichC. neoformans may elude the host immune response.

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Casadevall, Arturo. "Antibody immunity andCryptococcus neoformans." Canadian Journal of Botany 73, S1 (1995): 1180–86. http://dx.doi.org/10.1139/b95-376.

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Recently there has been renewed interest in the potential of antibody immunity for the prevention and therapy of human Cryptococcus neoformans infections. Historically, the role of antibody immunity in protection against C. neoformans has been controversial. Experiments with polyclonal sera have produced evidence for and against the importance of antibody immunity in host defence. However, three groups have now shown that administration of monoclonal antibody (mAb) to the C. neoformans capsular polysaccharide (CPS) can modify the course of infection in mice. The quantity, isotype, and specificity of mAb appear to be important parameters of antibody efficacy against C. neoformans. Protective and nonprotective mAbs to CPS have been identified, suggesting a possible explanation for the divergent results obtained with polyclonal preparations, which presumably contain both types of antibodies. mAb administration has been shown to prolong survival, decrease organ fungal burden, and reduce serum polysaccharide antigen. The mechanism(s) by which mAb modify the course of infection is uncertain. In vitro experiments strongly suggest that antibodies mediate protection by enhancing effector cell function. The combination of antibody and amphotericin B is more effective than either agent alone for the treatment of murine cryptococcosis. Human–mouse chimeric antibodies with activity against C. neoformans have been constructed that may have advantages over mouse mAbs for therapy of human infections. A highly immunogenic capsular polysaccharide–protein vaccine has been made that can elicit protective antibodies in mice. Antibody immunity can modify the course of infection to the benefit of the host and may be useful in the prevention and treatment of human cryptococcosis. Key words: antibody, Cryptococcus neoformans, macrophage, vaccine, AIDS.

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Gutierrez Garcia, Elizabeth, and Ortega Martinez Ortega Martinez. "CCCerebral cryptococcosis regarding two clinical cases and bibliographic review." Salud, Ciencia y Tecnología - Serie de Conferencias 3 (April 9, 2024): 679. http://dx.doi.org/10.56294/sctconf2024679.

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Cryptococcosis is a life-threatening infection, the species complexes Cryptococcus neoformans and Cryptococcus gattii are yeasts with a polysaccharide capsule, metabolize urea and catecholamines; It is transmitted by inhalation of bird droppings, mainly pigeons, and is capable of causing outbreaks in both immunocompromised and immunocompetent hosts. In Latin America, cryptococcal meningitis is a health threat. The initial infection is localized to the lungs and spreads to other organs, such as the central nervous system, where it causes meningoencephalitis and rarely focal granulomatous lesions such as cryptococcomas. The diagnosis must be made early, with serological tests for the cryptococcal polysaccharide capsular antigen. Treatment is divided into induction, consolidation and maintenance. Below, two clinical cases are presented, the first case is a 68-year-old female with a history of tuberculosis 15 years ago; 10 days, with holocranial headache, nausea and vomiting; on physical examination with superficial stupor, nuchal rigidity; kerning sign (+); lumbar puncture with identification of cryptococcal meningitis, induction treatment with fluconazole was started. The second case, a 60-year-old male with a history of acute lymphoblastic leukemia with chemotherapy 1 month ago, suddenly presented with altered consciousness, a lumbar puncture was performed, which reported cryptococcal meningitis by PCR, induction treatment with fluconazole was started; Both patients were admitted to the Intensive Care Unit, however, they had an unfavorable outcome.

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dos Santos, Matheus Henrique, Michele Procópio Machado, Pappanaicken R. Kumaresan, and Thiago Aparecido da Silva. "Titan Cells and Yeast Forms of Cryptococcus neoformans and Cryptococcus gattii Are Recognized by GXMR-CAR." Microorganisms 9, no. 9 (2021): 1886. http://dx.doi.org/10.3390/microorganisms9091886.

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Cryptococcosis, a systemic mycosis that affects both the immunocompromised and immunocompetent, is caused by the inhalation of dehydrated yeasts or fungal spores of Cryptococcus gattii or Cryptococcus neoformans. The Cryptococcus spp. polysaccharide capsule is composed mainly of glucuronoxylomannan—GXM, its major virulence factor. The capsule thickness increases to more than 15 μm during titanization, favoring the pathogenesis of cryptococcosis. Previous studies demonstrated that cytotoxic T cells that had been bioengineered with GXM-targeting chimeric antigen receptor (GXMR-CAR) were able to recognize C. neoformans by promoting the control of titanization. GXMR-CAR, a second-generation CAR, contains a single-chain variable fragment that originates from a 18B7 clone: a human IgG4 hinge, followed by a human CD28 (transmembrane/cytoplasmic domains) and a CD3ς chain. In the current study, we redirected T cells to target distinct C. neoformans and C. gattii cell types by GXMR-CAR. Lentiviral particles carrying the GXMR-CAR sequence were used to transduce Jurkat cells, and these modified cells interacted with the GXM of the C. gattii R265 strain. Moreover, GXMR-CAR mediated the recognition of C. gattii and C. neoformans yeasts with both thin and thick polysaccharide capsules, and GXMR-CAR Jurkat cells interacted with titan cells sourced from both Cryptococcus spp. Thus, bioengineered cells using CAR can improve the treatment of cryptococcosis.

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Gazzoni, Alexandra Flávia, Cecília Bittencourt Severo, Emily Ferreira Salles, and Luiz Carlos Severo. "Histopathology, serology and cultures in the diagnosis of cryptococcosis." Revista do Instituto de Medicina Tropical de São Paulo 51, no. 5 (2009): 255–59. http://dx.doi.org/10.1590/s0036-46652009000500004.

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Cryptococcosis is one of the most common opportunistic fungal infections in patients with acquired immunodeficiency syndrome (AIDS). We report 13 cases of cryptococcal infection based on histopathology, serology and cultures. Epidemiological analysis, histochemical techniques of hematoxilin and eosin (HE) and Grocot's silver (GMS), as well special histochemical techniques such as Mayer's mucicarmine (MM) and Fontana-Masson (FM), cryptococcal antigen test (CrAg) and isolation on fungal media: Sabouraud's (SAB), brain-heart infusion agar (BHI) and canavanine-glycine-bromothymol blue (CGB) agar were analyzed. Unsatisfactory staining results by MM stain associated to negative titers by CrAg test, which FM stain confirmed that capsule-deficient Cryptococcus infections were observed in four cases. Eight isolated cases were identified as follows: six cases were infection with Cryptococcus neoformans and two cases were Cryptococcus gattii.

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Hamilton, A. J., M. A. Bartholomew, J. Figueroa, L. E. Fenelon, and R. J. Hay. "Murine monoclonal antibodies recognizing a non-capsular antigen that distinguishes between Cryptococcus neoformans var. neoformans and C. neoformans var. gattii." Transactions of the Royal Society of Tropical Medicine and Hygiene 85, no. 1 (1991): 123–27. http://dx.doi.org/10.1016/0035-9203(91)90184-z.

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Lupo, P., Y. C. Chang, B. L. Kelsall, et al. "The Presence of Capsule in Cryptococcus neoformans Influences the Gene Expression Profile in Dendritic Cells during Interaction with the Fungus." Infection and Immunity 76, no. 4 (2008): 1581–89. http://dx.doi.org/10.1128/iai.01184-07.

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ABSTRACT The aim of this investigation was to study the effect of polysaccharide capsule on the gene expression in dendritic cells (DC) during their interaction with Cryptococcus neoformans. To this end, we used an encapsulated virulent strain of C. neoformans and a cap59 gene-disrupted acapsular avirulent strain derived from the same genetic background. DC were exposed to encapsulated and acapsular C. neoformans strains for 4 h and 18 h, and their transcriptional profiles were analyzed using the Affymetrix mouse gene chip U74Av2. A large number of DC genes were up-regulated after treatment with the acapsular strain. In particular, we observed the up-regulation of the genes involved in DC maturation, such as cell surface receptors, cytokines, and chemokines (interleukin-12 [IL-12], IL-2, IL-1α, IL-1β, IL-6, IL-10, tumor necrosis factor alpha, CCR7, CCL17, CCL22, CCL3, CCL4, CCL7, and CXCL10), membrane proteins, and the genes involved in antigen processing and presentation as well as cell cycle or apoptosis. The chemokine gene expression data were confirmed by real-time reverse transcription-PCR, while the expression of cytokine genes was correlated with their secretion. A completely different pattern of gene expression was observed for DC treated with an encapsulated strain of C. neoformans. In particular, no significant induction was observed in the expression of the genes mentioned above. Moreover, a number of genes, such as those coding for chemokines, were down-regulated. These results suggest that the polysaccharide capsule shrouding the cell wall of C. neoformans plays a fundamental role in inducing DC response, highlighting the molecular basis of the true nature of immune silencing exerted by capsular material.

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Syme, Rachel M., Tony F. Bruno, Thomas R. Kozel, and Christopher H. Mody. "The Capsule of Cryptococcus neoformans Reduces T-Lymphocyte Proliferation by Reducing Phagocytosis, Which Can Be Restored with Anticapsular Antibody." Infection and Immunity 67, no. 9 (1999): 4620–27. http://dx.doi.org/10.1128/iai.67.9.4620-4627.1999.

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ABSTRACT Cell-mediated immunity is critical for the host defense toCryptococcus neoformans, as demonstrated by numerous animal studies and the prevalence of the infection in AIDS patients. Previous studies have established that the polysaccharide capsule contributes to the virulence of C. neoformans by suppressing T-lymphocyte proliferation, which reflects the clonal expansion of T lymphocytes that is a hallmark of cell-mediated immunity. The present studies were performed to identify the major mechanism by which polysaccharide impairs lymphocyte proliferation, since capsular polysaccharide has the potential to affect the development of T-lymphocyte responses by stimulating production of interleukin-10 (IL-10), inhibiting phagocytosis, and inducing shedding of cell surface receptors. We demonstrate that polysaccharide inhibits lymphocyte proliferation predominantly by blocking uptake of C. neoformans, which is crucial for subsequent lymphocyte proliferation. In addition, we show that polysaccharide did not suppress lymphocyte proliferation via an IL-10-dependent mechanism, nor did it affect critical surface receptor interactions on the T cell or antigen-presenting cell. Having established that polysaccharide impairs phagocytosis, we performed studies to determine whether opsonization with human serum or with anticapsular antibody could reverse this effect. Impaired uptake and lymphocyte proliferation that were induced by polysaccharide can be enhanced through opsonization with monoclonal antibodies or human serum, suggesting that antipolysaccharide antibodies might enhance the host defense by restoring uptake of the organism and subsequent presentation to T lymphocytes. These studies support the therapeutic potential of stimulating cell-mediated immunity to C. neoformans with anticapsular antibody.

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Mahajan, Kedar R., Amity L. Roberts, Mark T. Curtis, Danielle Fortuna, Robin Dharia, and Lori Sheehan. "Diagnostic Challenges ofCryptococcus neoformansin an Immunocompetent Individual Masquerading as Chronic Hydrocephalus." Case Reports in Neurological Medicine 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/7381943.

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Cryptococcus neoformanscan cause disseminated meningoencephalitis and evade immunosurveillance with expression of a major virulence factor, the polysaccharide capsule. Direct diagnostic assays often rely on the presence of the cryptococcal glucuronoxylomannan capsular antigen (CrAg) or visualization of the capsule. Strain specific phenotypic traits and environmental conditions influence differences in expression that can thereby compromise detection and timely diagnosis. Immunocompetent hosts may manifest clinical signs and symptoms indolently, often expanding the differential and delaying appropriate treatment and diagnosis. We describe a 63-year-old man who presented with a progressive four-year history of ambulatory dysfunction, headache, and communicating hydrocephalus. Serial lumbar punctures (LPs) revealed elevated protein (153–300 mg/dL), hypoglycorrhachia (19–47 mg/dL), lymphocytic pleocytosis (89–95% lymphocyte, WBC 67–303 mg/dL, and RBC 34–108 mg/dL), and normal opening pressure (13–16 cm H2O). Two different cerebrospinal fluid (CSF) CrAg assays were negative. A large volume CSF fungal culture grew unencapsulatedC. neoformans. He was initiated on induction therapy with amphotericin B plus flucytosine and consolidation/maintenance therapy with flucytosine, but he died following discharge due to complications. Elevated levels of CSF Th1 cytokines and decreased IL6 may have affected the virulence and detection of the pathogen.

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Casadevall, Arturo, Wendy Cleare, Marta Feldmesser, et al. "Characterization of a Murine Monoclonal Antibody toCryptococcus neoformans Polysaccharide That Is a Candidate for Human Therapeutic Studies." Antimicrobial Agents and Chemotherapy 42, no. 6 (1998): 1437–46. http://dx.doi.org/10.1128/aac.42.6.1437.

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ABSTRACT The murine monoclonal antibody (MAb) 18B7 [immunoglobulin G1(κ)] is in preclinical development for treatment ofCryptococcus neoformans infections. In anticipation of its use in humans, we defined the serological and biological properties of MAb 18B7 in detail. Structural comparison to the related protective MAb 2H1 revealed conservation of the antigen binding site despite several amino acid differences. MAb 18B7 was shown by immunofluorescence and agglutination studies to bind to all four serotypes of C. neoformans, opsonize C. neoformans serotypes A and D, enhance human and mouse effector cell antifungal activity, and activate the complement pathway leading to deposition of complement component 3 (C3) on the cryptococcal capsule. Administration of MAb 18B7 to mice led to rapid clearance of serum cryptococcal antigen and deposition in the liver and spleen. Immunohistochemical studies revealed that MAb 18B7 bound to capsular glucuronoxylomannan in infected mouse tissues. No reactivity of MAb 18B7 with normal human, rat, or mouse tissues was detected. The results show that both the variable and constant regions of MAb 18B7 are biologically functional and support the use of this MAb in human therapeutic trials.

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Gupta, R. K., Z. U. Khan, M. R. N. Nampoory, M. M. Mikhail, and K. V. Johny. "Cutaneous cryptococcosis in a diabetic renal transplant recipient." Journal of Medical Microbiology 53, no. 5 (2004): 445–49. http://dx.doi.org/10.1099/jmm.0.05362-0.

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A diabetic renal transplant recipient with cellulitis caused by Cryptococcus neoformans, serotype A, is described. The diagnosis was based on the demonstration of capsulated, budding yeast cells in the aspirated material and tissue from the cellulitic lesion and isolation of the aetiological agent in culture. The isolate formed well-developed capsules in the brain tissue of experimentally infected mice and produced cherry-brown colonies on niger seed medium. The patient's serum was positive for cryptococcal antigen (titre 1 : 4) with no other evidence of systemic infection. He was successfully treated with AmBisome, followed by fluconazole, resulting in the complete resolution of cellulitis and disappearance of the cryptococcal antigen. This report underscores the fact that patients with cutaneous cryptococcosis should be thoroughly evaluated, as it may be the first manifestation of a systemic disease. Prompt diagnosis and treatment are important to improve survival.

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Garber, Sarah T., and Paul L. Penar. "Treatment of indolent, nonencapsulated cryptococcal meningitis associated with hydrocephalus." Clinics and Practice 2, no. 1 (2012): 22. http://dx.doi.org/10.4081/cp.2012.e22.

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Infection with cryptococcal meningitis is uncommon in immunocompetent patients. The major virulence factor is the polysaccharide capsule, while nonencapsulated mutants are generally considered nonpathogenic. The authors present a case of hydrocephalus caused by meningitis from an indolent, nonencapsulated Cryptococcus sp. requiring placement and multiple revisions of a ventriculoperitoneal shunt (VPS). The patient presented with progressively worsening occipital headaches. Computed tomography and magnetic resonance imaging showed significant hydrocephalus with no apparent cause. Her symptoms initially resolved after placement of a VPS, but returned four months later. Cultures of the shunt tubing and cerebrospinal fluid (CSF) showed no bacterial infection. When the symptoms failed to resolve, CSF fungal culture revealed Cryptococcus-like yeast, although the organisms were nonencapsulated, and the cryptococcal antigen was negative. After antibiotic therapy, the symptoms resolved. The unusual clinical presentation delayed the diagnosis, highlighting the importance of understanding the detection, diagnosis, and treatment of meningeal infections caused by C. neoformans.

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Kumaresan, Pappanaicken, Thiago daSilva, and Tamara Laskowski. "Glucuronoxylomannan in the Cryptococcus species capsule as a target for CAR+ T-cell therapy." Journal of Immunology 204, no. 1_Supplement (2020): 231.26. http://dx.doi.org/10.4049/jimmunol.204.supp.231.26.

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Abstract The genus Cryptococcus comprises two major fungal species that cause clinical infections in humans: C. gattii and C. neoformans. Each year, about 1 million cases of Cryptococcus infection are reported worldwide, and the infection’s mortality rate ranges from 20% to 70%. To combat the cryptococcosis, we proposed the redirection of CD8+ T cells to target glucuronoxylomannan (GXM), a sugar present in the Cryptococcus species capsule, via expression of a GXM-specific chimeric antigen receptor (GXMR-CAR) for treatment of cryptococcosis. GXMR-CAR has an anti-GXM single-chain variable fragment followed by an IgG4 stalk, a CD28 transmembrane domain, and CD3-zeta and CD28 signaling domains. After lentiviral transduction of human T cells with the GXMR-CAR construct, flow cytometry demonstrated that 82.4% of the cells expressed GXMR-CAR on their surface. To determine whether the GXMR-CAR+ T cells exhibited GXM-specific recognition, these cells were incubated with GXM for 24 h and examined using bright-field microscopy. Large clusters of proliferating GXMR-CAR+ T cells were observed, while no clusters were present in the control cells. The ability of GXMR-CAR T cells to bind to the yeast form of C. neoformans was detected by flow cytometry and fluorescent microscopy, but no binding was detected in mock-transduced control T cell (NoDNA T cells). Furthermore, when GXMR-CAR+ T cells were administered to immunocompromised NSG mice infected with C. neoformans their C. neoformans burden was significantly lower than mock-transduced control T cell treated mice as shown via immunofluorescence using an anti-GXM antibody and Gomori methenamine-silver (GMS) staining of Titan cells in lung tissue.

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Maitta, Robert W., Kausik Datta, Andrew Lees, Shelley Sims Belouski, and Liise-anne Pirofski. "Immunogenicity and Efficacy of Cryptococcus neoformans Capsular Polysaccharide Glucuronoxylomannan Peptide Mimotope-Protein Conjugates in Human Immunoglobulin Transgenic Mice." Infection and Immunity 72, no. 1 (2004): 196–208. http://dx.doi.org/10.1128/iai.72.1.196-208.2004.

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ABSTRACT Peptide mimotopes of capsular polysaccharides have been proposed as antigens for vaccines against encapsulated pathogens. In this study, we determined the antibody response to and efficacy of P13, a peptide mimetic of the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM), in mice that produce human antibodies. P13 was conjugated to tetanus toxoid (TT) or diphtheria toxoid (DT) and administered subcutaneously in Alhydrogel with or without CpG to mice transgenic for human immunoglobulin loci (XenoMouse mice) and expressing either immunoglobulin G2 (IgG2) (G2 mice) or IgG4 (G4 mice). Mice were vaccinated and revaccinated two or three times. The serum antibody responses of the mice to GXM and P13 and antibody idiotype expression were analyzed by an enzyme-linked immunosorbent assay. The results showed that both P13-TT and P13-DT were antigenic, inducing a mimetic response to P13 in both G2 and G4 mice, and immunogenic, inducing a mimotope response including VH3 (idiotype)-positive antibodies to GXM in G2 but not G4 mice. CpG led to higher titers of IgG to P13 and GXM in P13-TT-vaccinated G2 mice. C. neoformans challenge of P13-protein conjugate-vaccinated and control G2 mice induced anamnestic IgG- and VH3-positive responses to GXM and was associated with a significantly decreased risk of death and a prolongation of survival in P13-DT-vaccinated mice compared to phosphate-buffered saline-treated or protein carrier-vaccinated mice. These findings reveal that P13 elicited a human antibody response with VH3 expression in human immunoglobulin transgenic mice that has been observed for human antibodies to GXM and support the concept that peptide mimotope-based vaccines may hold promise for the treatment of C. neoformans infections.

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Beardsley, Justin, Tania C. Sorrell, and Sharon C. A. Chen. "Central Nervous System Cryptococcal Infections in Non-HIV Infected Patients." Journal of Fungi 5, no. 3 (2019): 71. http://dx.doi.org/10.3390/jof5030071.

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Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is caused by Cryptococcus neoformans and Cryptococcus gattii species complex; C. gattii is endemic in several geographic regions and has caused outbreaks in North America. Major virulence determinants are the polysaccharide capsule, melanin and several ‘invasins’. Cryptococcal plb1, laccase and urease are essential for dissemination from lung to CNS and crossing the blood–brain barrier. Meningo-encephalitis is common but intracerebral infection or hydrocephalus also occur, and are relatively frequent in C. gattii infection. Complications include neurologic deficits, raised intracranial pressure (ICP) and disseminated disease. Diagnosis relies on culture, phenotypic identification methods, and cryptococcal antigen detection. Molecular methods can assist. Preferred induction antifungal therapy is a lipid amphotericin B formulation (amphotericin B deoxycholate may be used in non-transplant patients) plus 5-flucytosine for 2–6 weeks depending on host type followed by consolidation/maintenance therapy with fluconazole for 12 months or longer. Control of raised ICP is essential. Clinicians should be vigilant for immune reconstitution inflammatory syndrome.

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Meena, Priti, Vinant Bhargava, Kulwant Singh, Jasmine sethi, Aniketh Prabhakar, and Sandip panda. "Cryptococcosis in kidney transplant recipients: Current understanding and practices." World Journal of Nephrology 12, no. 5 (2023): 120–31. http://dx.doi.org/10.5527/wjn.v12.i5.120.

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Cryptococcosis is the third most commonly occurring invasive fungal disease in solid organ transplant recipients (SOT). It is caused by encapsulated yeast, Cryptococcus species, predominantly Cryptococcus neoformans and Cryptococcus gattii. Though kidney transplant recipients are at the lowest risk of cryptococcosis when compared to other solid organ transplant recipients such as lung, liver or heart, still this opportunistic infection causes significant morbidity and mortality in this subset of patients. Mortality rates with cryptococcosis range from 10%-25%, while it can be as high as 50% in SOT recipients with central nervous system involvement. The main aim of diagnosis is to find out if there is any involvement of the central nervous system in disseminated disease or whether there is only localized pulmonary involvement as it has implications for both prognostication and treatment. Detection of cryptococcal antigen (CrAg) in cerebrospinal fluid or plasma is a highly recommended test as it is more sensitive and specific than India ink and fungal cultures. The CrAg lateral flow assay is the single point of care test that can rapidly detect cryptococcal polysaccharide capsule. Treatment of cryptococcosis is challenging in kidney transplant recipients. Apart from the reduction or optimization of immunosuppression, lipid formulations of amphotericin B are preferred as induction antifungal agents. Consolidation and maintenance are done with fluconazole; carefully monitoring its interactions with calcineurin inhibitors. This review further discusses in depth the evolving developments in the epidemiology, pathogenesis, diagnostic assays, and management approach of cryptococcosis in kidney transplant recipients.

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dos Santos, Matheus Henrique, Michele Procópio Machado, Pappanaicken R. Kumaresan, and Thiago Aparecido da Silva. "Modification of Hinge/Transmembrane and Signal Transduction Domains Improves the Expression and Signaling Threshold of GXMR-CAR Specific to Cryptococcus spp." Cells 11, no. 21 (2022): 3386. http://dx.doi.org/10.3390/cells11213386.

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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.

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Melcher, Gregory P., Michael G. Rinaldi, Carrie L. Frey, and David J. Drutz. "Demonstration, by Immunoelectronmicroscopy, of a Cell Wall Antigen in Trichosporon beigelii That Cross-Reacts with Cryptococcus neoformans Capsular Polysaccharide." Journal of Infectious Diseases 158, no. 4 (1988): 901–2. http://dx.doi.org/10.1093/infdis/158.4.901.

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Valadon, Philippe, Gabriel Nussbaum, Jin Oh, and Matthew D. Scharff. "Aspects of Antigen Mimicry Revealed by Immunization with a Peptide Mimetic of Cryptococcus neoformans Polysaccharide." Journal of Immunology 161, no. 4 (1998): 1829–36. http://dx.doi.org/10.4049/jimmunol.161.4.1829.

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Abstract We have recently identified peptide mimetics of the Cryptococcus neoformans capsular polysaccharide by screening phage display peptide libraries. 2H1, one of a large family of mAbs against the glucuronoxylomannan fraction (GXM), is highly protective and binds several peptide motifs. This study analyzes the immunologic properties of P601E (SYSWMYE), a peptide from the low affinity motif (W/YXWM/LYE) that has an extended cross-reactivity among anti-GXM mAbs and whose binding correlates with the protective potential of mAbs in experimental infection. P601E is a mimetic, since it competes for GXM binding to 2H1, but not a mimotope, since it does not elicit an anti-GXM response. Sequence analysis of 14 anti-P601E mAbs indicates that anti-P601E mAbs elicited in BALB/c mice have an order of homology with 2H1 of Vκ &gt; Jκ ≫ VH &gt; JH &gt; D. Further screening of a peptide library with anti-P601E mAbs isolated peptides having a motif almost identical to the peptide motif selected by 2H1. When these results are compared to the crystal structure of a related peptide in complex with 2H1, there is a clear correlation between the ability to elicit V region components of 2H1 Ab and peptide association with the V region, suggesting that the completeness of the fit in the binding site is an important driving force for mimicry. As a consequence, improving affinity of a mimetic for the Ab binding site seems to be the most logical way to insure that all of the appropriate V region segments are elicited and that useful mimotopes are created.

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Percival, Ann, Peter Thorkildson, and Thomas R. Kozel. "Monoclonal Antibodies Specific for Immunorecessive Epitopes of Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans, Reduce Serotype Bias in an Immunoassay for Cryptococcal Antigen." Clinical and Vaccine Immunology 18, no. 8 (2011): 1292–96. http://dx.doi.org/10.1128/cvi.05052-11.

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ABSTRACTImmunoassay for detection of glucuronoxylomannan (GXM), the major capsular polysaccharide ofCryptococcus neoformans, is an important tool for diagnosis of cryptococcosis. However, immunoassays that are based solely or in part on detection with polyclonal antibodies may show serotype bias in detection of GXM, particularly limited sensitivity for serotype C. In this study, we describe detection of GXM in an antigen capture sandwich enzyme-linked immunosorbent assay (ELISA) that used a cocktail of two monoclonal antibodies (MAbs). MAb F12D2 was previously produced by immunization with GXM that had been treated to removeO-acetyl groups, a major source of serotype specificity. MAb F12D2 has a high degree of reactivity with GXM of serotypes A, B, C, and D, but the reactivity with serotype D was less than was found with other MAbs. MAb 339 is highly reactive with GXM of serotypes A and D. Use of a combination of the two MAbs produced an immunoassay that had the best properties of both MAbs, including good reactivity with serotype C, which is an emerging threat in sub-Saharan Africa. These results suggest that next-generation immunoassays for diagnosis of cryptococcosis may be formulated by (i) use of immunization and hybridoma screening strategies that are designed to prospectively meet the needs of immunoassay performance and (ii) careful selection of MAbs that span the expected polysaccharide serotypes in the subject patient population.

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Costa, Maurimelia, Lucimar Madeira, Rosimar Feitosa, et al. "Detection of Cryptococcus neoformans Capsular Antigen in HIV-Infected Patients in the State of Para in the North of Brazil." Current HIV Research 11, no. 8 (2014): 647–51. http://dx.doi.org/10.2174/1570162x12666140311125420.

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Larsen, Robert A., Peter G. Pappas, John Perfect, et al. "Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis." Antimicrobial Agents and Chemotherapy 49, no. 3 (2005): 952–58. http://dx.doi.org/10.1128/aac.49.3.952-958.2005.

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ABSTRACT A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.

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Pacifici, Noah, Melissa Cruz-Acuña, Agustina Diener, et al. "Vomocytosis of Cryptococcus neoformans cells from murine, bone marrow-derived dendritic cells." PLOS ONE 18, no. 3 (2023): e0280692. http://dx.doi.org/10.1371/journal.pone.0280692.

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Cryptococcus neoformans (CN) cells survive within the acidic phagolysosome of macrophages (MΦ) for extended times, then escape without impacting the viability of the host cell via a phenomenon that has been coined ‘vomocytosis’. Through this mechanism, CN disseminate throughout the body, sometimes resulting in a potentially fatal condition—Cryptococcal Meningitis (CM). Justifiably, vomocytosis studies have focused primarily on MΦ, as alveolar MΦ within the lung act as first responders that ultimately expel this fungal pathogen. Herein, we hypothesize that dendritic cells (DCs), an innate immune cell with attributes that include phagocytosis and antigen presentation, can also act as ‘vomocytes’. Presciently, this report shows that vomocytosis of CN indeed occurs from murine, bone marrow-derived DCs. Primarily through time-lapse microscopy imaging, we show that rates of vomocytosis events from DCs are comparable to those seen from MΦ and further, are independent of the presence of the CN capsule and infection ratios. Moreover, the phagosome-altering drug bafilomycin A inhibits this phenomenon from DCs. Although DC immunophenotype does not affect the total number of vomocytic events, we observed differences in the numbers of CN per phagosome and expulsion times. Interestingly, these observations were similar in murine, bone marrow-derived MΦ. This work not only demonstrates the vomocytic ability of DCs, but also investigates the complexity of vomocytosis regulation in this cell type and MΦ under multiple modulatory conditions. Understanding the vomocytic behavior of different phagocytes and their phenotypic subtypes is needed to help elucidate the full picture of the dynamic interplay between CN and the immune system. Critically, deeper insight into vomocytosis could reveal novel approaches to treat CM, as well as other immune-related conditions.

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Baronetti, José L., Laura S. Chiapello, Ana P. Garro, and Diana T. Masih. "Differential Activation of Peritoneal Cells by Subcutaneous Treatment of Rats with Cryptococcal Antigens." Clinical and Vaccine Immunology 16, no. 8 (2009): 1213–21. http://dx.doi.org/10.1128/cvi.00100-09.

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ABSTRACT Previous studies in our laboratory have shown that the subcutaneous pretreatment of rats with heat-killed cells (HKC) of Cryptococcus neoformans emulsified in complete Freund adjuvant (CFA) promotes protective immunity against an intraperitoneal challenge with C. neoformans. In contrast, subcutaneous treatment with the capsular polysaccharide (PSC) emulsified in CFA exacerbates the cryptococcal infection. The purpose of this study was to analyze the mechanisms involved in these phenomena. Adherent peritoneal cells from rats treated with HKC-CFA showed upregulated ED2, CD80, and CD86 expression; an increase in the level of production of anticryptococcal metabolites; and the enhanced production of interleukin-12 (IL-12) in comparison with the findings for cells from rats treated with CFA-phosphate-buffered saline (PBS). Adherent peritoneal cells from rats treated with PSC-CFA, however, also presented upregulated ED2, CD80, and CD86 expression compared to the level of expression for peritoneal cells from controls, but these cells showed an increase in arginase activity and decreased levels of production of IL-12 and tumor necrosis factor (TNF) compared with the activity and levels of production by peritoneal cells from CFA-PBS-treated rats. In addition, treatment with HKC-CFA resulted in a rise in the phagocytic and anticryptococcal activities of adherent peritoneal cells compared to those for control rats. However, adherent peritoneal cells from rats treated with PSC-CFA presented a reduction in anticryptococcal activity in comparison with that for cells from animals treated with CFA-PBS. These results show the differential activation between adherent peritoneal cells from HKC-CFA- and PSC-CFA-treated rats, with this differential activation at the primary site of infection possibly being responsible, at least in part, for the phenomena of protection and exacerbation observed in our model.

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McManus, E. J., and J. M. Jones. "Detection of a Trichosporon beigelii antigen cross-reactive with Cryptococcus neoformans capsular polysaccharide in serum from a patient with disseminated Trichosporon infection." Journal of Clinical Microbiology 21, no. 5 (1985): 681–85. http://dx.doi.org/10.1128/jcm.21.5.681-685.1985.

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Blackstock, Rebecca, Kent L. Buchanan, Adekunle M. Adesina, and J. W. Murphy. "Differential Regulation of Immune Responses by Highly and Weakly Virulent Cryptococcus neoformansIsolates." Infection and Immunity 67, no. 7 (1999): 3601–9. http://dx.doi.org/10.1128/iai.67.7.3601-3609.1999.

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Early inflammatory responses, delayed-type hypersensitivity (DTH) responses, and cytokine profiles were studied in mice infected by the pulmonary route with either a highly virulent isolate (NU-2) or a weakly virulent isolate (184A) of Cryptococcus neoformans. After infection, NU-2 remained in the lungs and the capsule became more pronounced during the first 24 h, whereas 184A induced an immediate inflammatory reaction and was rapidly cleared from the lungs. Cryptococcal antigen (GXM) appeared in sera early after infection with NU-2 and increased over the entire observation period. There was no detectable GXM in sera from 184A-infected mice. Both C. neoformans isolates induced anticryptococcal cell-mediated immune responses, but the responses had different profiles. DTH in NU-2-infected mice appeared at day 15 after infection and waned by day 21, whereas DTH in 184A-infected mice was present by day 5 and continued to increase. T helper 1 (Th1) cytokines (interleukin 2 [IL-2] and gamma interferon) were made by spleen cells early after infection with either isolate. NU-2-infected mice lost their ability to produce these cytokines, but 184A-infected mice retained it. IL-4, a Th2 cytokine, was not detected in infected mice. The regulatory cytokine IL-10 was made by spleen cells early but not later after infection with the highly virulent isolate and was not produced by spleen cells from 184A-infected mice. IL-10-deficient mice survived an NU-2 infection significantly longer than wild-type mice, suggesting that IL-10 is important in down-regulating the protective immune response. The induction of anergy appears to be responsible for the inability of NU-2-infected mice to control a C. neoformansinfection.

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Vecchiarelli, Anna, Donatella Pietrella, Francesco Bistoni, Thomas R. Kozel, and Arturo Casadevall. "Antibody to Cryptococcus neoformans capsular glucuronoxylomannan promotes expression of interleukin-12Rbeta2 subunit on human T cells in vitro through effects mediated by antigen-presenting cells." Immunology 106, no. 2 (2002): 267–72. http://dx.doi.org/10.1046/j.1365-2567.2002.01419.x.

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Macura, Nataša, Tong Zhang, and Arturo Casadevall. "Dependence of Macrophage Phagocytic Efficacy on Antibody Concentration." Infection and Immunity 75, no. 4 (2007): 1904–15. http://dx.doi.org/10.1128/iai.01258-06.

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ABSTRACT Macrophages ingest the fungus Cryptococcus neoformans only in the presence of opsonins, and this provides a remarkably clean system for the detailed analysis of phagocytosis. This system is also unusual in that antibody-mediated phagocytosis involves ingestion through both Fc and complement receptors in the absence of complement. Mathematical modeling was used to analyze and explain the experimental data that the macrophage phagocytic index increased with increasing doses of antibody despite saturating concentrations and declined at high concentrations. A model was developed that explains the increase in phagocytic index with increasing antibody doses, differentiates among the contributions from Fc and complement receptors, and provides a tool for estimating antibody concentrations that optimize efficacy of phagocytosis. Experimental results and model calculations revealed that blocking of Fc receptors by excess antibody caused a reduction in phagocytic index but increased phagocytosis through complement receptors rapidly compensated for this effect. At high antibody concentrations, a further reduction in phagocytic index was caused by interference with complement receptor ingestion as a consequence of saturation of the fungal capsule. The ability of our model to predict the antibody dose dependence of the macrophage phagocytic efficacy for C. neoformans strongly suggest that the major variables that determine the efficacy of this process have been identified. The model predicts that the affinity constant of the opsonic antibody for the Fc receptor and the association-dissociation constant of antibody from the microbial antigen are critical parameters determining the efficacy of phagocytosis.

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Avina, Samantha L., Siddhi Pawar, Amariliz Rivera, and Chaoyang Xue. "Will the Real Immunogens Please Stand Up: Exploiting the Immunogenic Potential of Cryptococcal Cell Antigens in Fungal Vaccine Development." Journal of Fungi 10, no. 12 (2024): 840. https://doi.org/10.3390/jof10120840.

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Cryptococcus neoformans is an opportunistic fungal pathogen that is a continuous global health concern, especially for immunocompromised populations. The World Health Organization recognized C. neoformans as one of four critical fungal pathogens, thus emphasizing the need for increased research efforts and clinical resource expansion. Currently, there are no fungal vaccines available for clinical use. Exciting new findings in cryptococcal vaccine development have identified whole cell-based and subunit-based vaccinations to help mitigate health risks and make commercialization attainable. Importantly, recent work has focused on how different cryptococcal cell-wall antigens modified in these vaccine candidates allow us to manipulate their immunogenicity to produce a desired long-term protective anti-fungal immune response. In this review, we discuss the different cryptococcal cell immunogens, namely the polysaccharide capsule, glucans, chitin/chitosan, mannoproteins, and extracellular vesicles, and their role in novel cryptococcal vaccination approaches. Additionally, we examine the immunological mechanisms responsible for protection in these vaccine candidates and the similar host response-stimulation pathways induced through different immunogen exposure.

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Nishiyama-Fujita, Y., Y. Xu, D. S. Kondapi, and G. R. Parkerson. "Primary Cutaneous Cryptococcosis of Nasal Ala with Extensive Tissue Destruction." American Journal of Clinical Pathology 156, Supplement_1 (2021): S49—S50. http://dx.doi.org/10.1093/ajcp/aqab191.100.

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Abstract Introduction/Objective Primary cutaneous cryptococcosis (PCC) is rare and shows skin lesion(s) confined to a circumscribed body region mostly in immunocompromised host, with no sign of simultaneous dissemination condition. PCC usually presents as non-specific skin lesions such as cellulitis, nodules, and ulcers, and can be misdiagnosed in biopsy. We present a case of PCC with extensive tissue destruction. Methods/Case Report A 43-year-old male, with a history of human immunodeficiency virus infection 17 years ago, presented with complaint of his nose slowly “being eaten away” over the past 5 years after a bike accident. Physical examination showed most of the left nasal ala was completely destroyed, with visualizable septum. The biopsy of the left nasal ala showed the dermis has numerous yeasts with marked variation in size and shape, in foamy stroma with little inflammation. The capsules of the yeasts were highlighted by Mucicarmine stain. Grocott methenamine silver stain showed budding yeasts. The diagnosis of cutaneous cryptococcosis, gelatinous type, was rendered. Primary cutaneous cryptococcosis was considered based on no disseminated disease found, positive serum cryptococcus antigen with low titer (1:20), the culture of the nasal lesion positive for Crptococcus Neoformans, and the history of skin injury. The patient received appropriate treatment for PCC subsequently. Results (if a Case Study enter NA) NA Conclusion We have demonstrated a very rare case of undiagnosed/untreated PCC causing extensive destruction of skin and underlying nasal tissue. Identification of the histological features of cutaneous cryptococcosis, shown in this case, is the key for making the correct diagnosis.

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Evans, E. Edward. "CAPSULAR REACTIONS OF CRYPTOCOCCUS NEOFORMANS*." Annals of the New York Academy of Sciences 89, no. 1 (2006): 184–92. http://dx.doi.org/10.1111/j.1749-6632.1960.tb20141.x.

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McFadden, Diane, Oscar Zaragoza, and Arturo Casadevall. "The capsular dynamics of Cryptococcus neoformans." Trends in Microbiology 14, no. 11 (2006): 497–505. http://dx.doi.org/10.1016/j.tim.2006.09.003.

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Franzot, Sarah P., Ira F. Salkin, and Arturo Casadevall. "Cryptococcus neoformans var.grubii: Separate Varietal Status for Cryptococcus neoformans Serotype A Isolates." Journal of Clinical Microbiology 37, no. 3 (1999): 838–40. http://dx.doi.org/10.1128/jcm.37.3.838-840.1999.

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Cryptococcus neoformans var. neoformanspresently includes isolates which have been determined by the immunologic reactivity of their capsular polysaccharides to be serotype A and those which have been determined to be serotype D. However, recent analyses of the URA5 sequences and DNA fingerprinting patterns suggest significant genetic differences between the two serotypes. Therefore, we propose to recognize these genotypic distinctions, as well as previously reported phenotypic differences, by restricting C. neoformans var. neoformans to isolates which are serotype D and describing a new variety, C. neoformans var. grubii, for serotype A isolates.

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Cherniak, R., and J. B. Sundstrom. "Polysaccharide antigens of the capsule of Cryptococcus neoformans." Infection and Immunity 62, no. 5 (1994): 1507–12. http://dx.doi.org/10.1128/iai.62.5.1507-1512.1994.

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White, Catherine W., and Eric S. Jacobson. "Mannosyl transfer in Cryptococcus neoformans." Canadian Journal of Microbiology 39, no. 1 (1993): 129–33. http://dx.doi.org/10.1139/m93-019.

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A particulate enzyme preparation from Cryptococcus neoformans transferred the mannosyl residue from GDP-mannose:o an acceptor consisting of a commercial preparation of methyl 3-O-α-mannopyranosyl-α-mannopyranoside (confining 10% 2-O-α-mannopyranosyl-α-mannopyranoside). The configuration of the new bond was alpha by its susceptibility to α-mannosidase; the amount of product was dependent on the concentration of enzyme, of GDP-mannose, and of acceptor. The optimal temperature and pH were 37 °C and 7.0, respectively. Manganous ion was required for activity and acetyl coenzyme A was stimulatory. Studies suggested that dolichyl phosphate intermediates were not involved in this mannose transfer. The fact that none of the several acapsular mutants tested were deficient in this mannosyltransferase suggested that this enzyme was not involved in synthesis of backbone mannan linkages in capsular polysaccharide. NMR analysis of the methylmannotriose product showed only α(1 → 2) linkages between sugar moieties. This mannosyltransferase evidently extends α(1 → 2) mannan by adding another α(1 → 2)-linked mannosyl residue. Its activity is appropriate for a role in synthesis of "high mannose" oligosaccharide moieties of glycoproteins.Key words: virulence, capsular polysaccharide, acapsular mutants, dolichol pathway, oligomannans.

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Castle, Sherry A., Elizabeth A. Owuor, Stephanie H. Thompson та ін. "β1,2-Xylosyltransferase Cxt1p Is Solely Responsible for Xylose Incorporation into Cryptococcus neoformans Glycosphingolipids". Eukaryotic Cell 7, № 9 (2008): 1611–15. http://dx.doi.org/10.1128/ec.00458-07.

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ABSTRACT The Manα1,3(Xylβ1,2)Manα structural motif is common to both capsular polysaccharides of Cryptococcus neoformans and to cryptococcal glycosphingolipids. Comparative analysis of glycosphingolipid structural profiles in wild-type and mutant strains showed that the Xylβ1,2-transferase (Cxt1p) that participates in capsular polysaccharide biosynthesis is also the sole transferase responsible for adding xylose to C. neoformans glycosphingolipids.

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Vecchiarelli, A. "Immunoregulation by capsular components of Cryptococcus neoformans." Medical Mycology 38, no. 6 (2000): 407–17. http://dx.doi.org/10.1080/714030973.

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Fonseca, Fernanda L., Leonardo Nimrichter, Radames J. B. Cordero, et al. "Role for Chitin and Chitooligomers in the Capsular Architecture of Cryptococcus neoformans." Eukaryotic Cell 8, no. 10 (2009): 1543–53. http://dx.doi.org/10.1128/ec.00142-09.

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ABSTRACT Molecules composed of β-1,4-linked N-acetylglucosamine (GlcNAc) and deacetylated glucosamine units play key roles as surface constituents of the human pathogenic fungus Cryptococcus neoformans. GlcNAc is the monomeric unit of chitin and chitooligomers, which participate in the connection of capsular polysaccharides to the cryptococcal cell wall. In the present study, we evaluated the role of GlcNAc-containing structures in the assembly of the cryptococcal capsule. The in vivo expression of chitooligomers in C. neoformans varied depending on the infected tissue, as inferred from the differential reactivity of yeast forms to the wheat germ agglutinin (WGA) in infected brain and lungs of rats. Chromatographic and dynamic light-scattering analyses demonstrated that glucuronoxylomannan (GXM), the major cryptococcal capsular component, interacts with chitin and chitooligomers. When added to C. neoformans cultures, chitooligomers formed soluble complexes with GXM and interfered in capsular assembly, as manifested by aberrant capsules with defective connections with the cell wall and no reactivity with a monoclonal antibody to GXM. Cultivation of C. neoformans in the presence of an inhibitor of glucosamine 6-phosphate synthase resulted in altered expression of cell wall chitin. These cells formed capsules that were loosely connected to the cryptococcal wall and contained fibers with decreased diameters and altered monosaccharide composition. These results contribute to our understanding of the role played by chitin and chitooligosaccharides on the cryptococcal capsular structure, broadening the functional activities attributed to GlcNAc-containing structures in this biological system.

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van de Wetering, J. K., F. E. J. Coenjaerts, A. B. Vaandrager, L. M. G. van Golde, and J. J. Batenburg. "Aggregation of Cryptococcus neoformans by Surfactant Protein D Is Inhibited by Its Capsular Component Glucuronoxylomannan." Infection and Immunity 72, no. 1 (2004): 145–53. http://dx.doi.org/10.1128/iai.72.1.145-153.2004.

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ABSTRACT Cryptococcus neoformans is an opportunistic pathogen invading the immunocompromised host. Infection starts with the inhalation of acapsular or sparsely encapsulated cells, after which capsule synthesis is initiated. The capsule is the main virulence factor of this yeast-like fungus. Pulmonary surfactant protein D (SP-D) is an important component of the local innate defense system. In the present study, interactions of SP-D with intact C. neoformans cells and their isolated capsular components were investigated. Although encapsulated cryptococci were bound, SP-D showed the highest affinity for acapsular C. neoformans. Only acapsular cryptococci were aggregated by SP-D. Furthermore, the cryptococcal capsular components glucuronoxylomannan (GXM) and mannoprotein 1 (MP1) were bound with relatively high affinity, in contrast to GalXM and MP2. Binding as well as aggregation of acapsular C. neoformans by SP-D could be inhibited by GXM in concentrations that are likely to be present in the lung after infection, suggesting that not only the capsule hampers SP-D function within the innate defense system of the lung but also the secreted capsular component GXM.

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Mozaffarian, N., J. W. Berman, and A. Casadevall. "Enhancement of nitric oxide synthesis by macrophages represents an additional mechanism of action for amphotericin B." Antimicrobial Agents and Chemotherapy 41, no. 8 (1997): 1825–29. http://dx.doi.org/10.1128/aac.41.8.1825.

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Amphotericin B (AmB) enhanced nitrite synthesis by murine macrophage-like J774.16 cells in a dose-dependent fashion. This effect was retained in the presence of Cryptococcus neoformans capsular polysaccharide, a known virulence factor. AmB and anticapsular antibody increased nitrite synergistically. In all cases, AmB required gamma interferon; C. neoformans cells were unable to elicit nitrite, with or without AmB.

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