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PubMed2006

Diversity of the T-cell response to pulmonary Cryptococcus neoformans infection.

Cell-mediated immunity plays an important role in immunity to the pathogenic fungus Cryptococcus neoformans. However, the antigen specificity of the T-cell response to C. neoformans remains largely unknown. In this study, we used two approaches to determine the antigen specificity of the T-cell response to C. neoformans. We report here that a diverse T-cell receptor (TCR) Vbeta repertoire was maintained throughout the primary response to pulmonary C. neoformans infection in immunocompetent mice. CD4+ T-cell deficiency resulted in relative expansion of all CD8+ T-cell subsets. During a secondary immune response, preferential usage of a TCR Vbeta subset in CD4+ T cells occurred in single individuals, but the preferences were "private" and not shared between individuals. Both CD4+ and CD8+ T cells from the secondary lymphoid tissues of immunized mice proliferated in response to a variety of C. neoformans antigens, including heat-killed whole C. neoformans, culture filtrate antigen, C. neoformans lysate, and purified cryptococcal mannoprotein. CD4+ and CD8+ T cells from the secondary lymphoid tissues of mice undergoing a primary response to C. neoformans proliferated in response to C. neoformans lysate. In response to stimulation with C. neoformans lysate, lung CD4+ and CD8+ T cells produced the effector cytokines tumor necrosis factor alpha and gamma interferon. These results demonstrate that a diverse T-cell response is generated in response to pulmonary C. neoformans infection.

Animals↗
PubMed1984

High prevalence of Cryptococcus neoformans var. gattii in tropical and subtropical regions.

The global distribution of 96 clinical isolates of Cryptococcus neoformans var. gattii among a total of 725 C. neoformans isolates was investigated. While C. neoformans var. gattii was not found among isolates obtained from Europe (excluding the United Kingdom) and Japan; and it was found only infrequently in North America (excluding Southern California), the United Kingdom, New Zealand, and Argentina; the variety was prevalent in regions with tropical to subtropical climates such as South East Asia, Southern California, Brazil, Mid to South Pacific, and the central part of Africa. Among the isolates of C. neoformans var. gattii in our collection, serotype B predominanted (77 of 96), and the serotype C isolates were almost exclusively from North America.

Africa↗
PubMed1994

Role of human alveolar macrophages as antigen-presenting cells in Cryptococcus neoformans infection.

The contribution of human alveolar macrophages (AM) from normal subjects in Cryptococcus neoformans infection was investigated. AM were able to efficiently phagocytize the fungus after opsonization, but killing activity did not occur at an effector-to-target ratio of 10:1 in a 6-h incubation since there was an inhibition of phagosome-lysosome fusion. Moreover, the role of AM as antigen-presenting cells was investigated. Cryptococcus-laden AM were co-cultured with autologous T lymphocytes and lymphoproliferation was determined; a massive blastogenic response of alpha/beta TCR-bearing T lymphocytes was observed. The response started after 1 day of co-culture and was triggered and regulated by IL-1 produced by AM in response to C. neoformans. Finally, the antigen-presentation process was associated with HLA class II DR molecules. This finding suggests that AM play a key role in the lung as antigen-presenting cells and, through the secretion of IL-1, regulate proliferation and activation of T lymphocytes, which are important in mediating pulmonary clearance. We speculate that in immunodepressive conditions, the impairment of AM functions could contribute to the spread of C. neoformans infection from the lung.

Adult↗
PubMed2004

Molecular epidemiology of Cryptococcus neoformans isolates from AIDS patients of the Brazilian city, Rio de Janeiro.

A high biodiversity of Cryptococcus neoformans isolates is known to exist in some Brazilian urban areas, raising the possibility that patients may encounter multiple inoculum sources in their daily life. C. neoformans isolates from two groups of AIDS patients with cryptococcosis from Rio de Janeiro were studied by polymerase chain reaction (PCR) fingerprinting and randomly amplified polymorphic DNA (RAPD) analysis. The first group contained 60 serial isolates obtained from 19 patients over periods ranging from 18 to 461 days; the intent was to determine whether the original strain persisted or whether reinfection with a new strain occurred. The second group was made up of 22 isolates from 11 patients, and consisted of a pair of isolates collected from blood and cerebrospinal fluid from each patient either before or shortly after treatment was initiated. The aim was to determine if the patient was infected by different strains simultaneously. All isolates were subtyped by PCR fingerprinting, using minisatellite (M13), and microsatellite [(GACA)4 and (GTG)5] specific primers, and RAPD analysis employing the combined primers 5SOR and CN1. The majority of isolates were C. neoformans var. grubii, specifically, molecular types VNI or VNII, but numerous distinguishable subtypes were found. Only three isolates were C. n. var. gattii (molecular types VGI or VGII). Except in two cases, all isolates obtained from the same patient showed identical PCR profiles independent of time of isolation or body site. Almost all patients, however, carried unique genotypes not found in any other patient. Our results confirm that persistent cryptococcal infection is caused by relapse rather than reinfection, but they also show that in exceptional cases, patients may be infected with more than one C. neoformans strain.

AIDS-Related Opportunistic Infections↗
PubMed2005

Isolation of Cryptococcus gattii and Cryptococcus neoformans var. grubii from the flowers and bark of Eucalyptus trees in India.

The association of Cryptococcus gattii with Eucalyptus trees has been well established. Here we report the isolation of both C. gattii and Cryptococcus neoformans var. grubii from the flowers and bark of Eucalyptus trees in India. We investigated a total of 233 samples of Eucalyptus trees: 120 flowers, 81 fragments of bark, and 32 leaves. C. gattii was isolated from two samples of flowers of Eucalyptus terreticornis. C. neoformans var. grubii was recovered twice from the bark of Eucalyptus camaldulensis, initially from one of three samples, and again 2 months later, from one of four samples collected beneath the canopy of the tree. The primary isolation medium was Nigerseed agar, and brown colonies were presumptively identified as C. gattii or C. neoformans. The species identification was confirmed by morphological and biochemical characteristics. Using the Crypto-Check kit (Iatron, Tokyo, Japan), the first two isolates were identified as serotype B (C. gattii) and the other two were serotype A (C. neoformans var. grubii). PCR analysis of the isolates of C. neoformans var. grubii revealed that they possessed the MATalpha mating type allele. Molecular typing by amplified fragment length polymorphism markers indicated that both isolates of C. neoformans var. grubii possessed the same genotype. This study demonstrates that C. neoformans var. grubii, as well as C. gattii, may be associated with Eucalyptus trees.

Cryptococcus neoformans↗
PubMedDate not supplied

Isolates of Cryptococcus neoformans serotype A and D developed on canavanine-glycine-bromthymol blue medium.

Two isolates of Cryptococcus neoformans serotype A and one isolate of serotype D from pigeon droppings were found to grow on canavanine-glycine-bromthymol blue (CGB) medium, when the Japanese isolates of Cr. neoformans were examined for their serotype and biochemical characteristics. The susceptibility to canavanine and the activity in assimilation of glycine were analysed on these three isolates. They were resistant to canavanine at the high concentration of 3.6 mmol l-1 and developed by assimilating the glycine even at a concentration of 7 mmol l-1. These isolates were proved to develop well on CGB medium, which contains 0.1 mmol l-1 of canavanine and 133 mmol l-1 of glycine. Three isolates of Cr. neoformans developed on CGB medium were also confirmed to be serotype A or D by the molecular analysis.

Animals↗
PubMed1995

Electrophoretic karyotype and in vitro antifungal susceptibility of Cryptococcus neoformans isolates from AIDS patients.

Electrophoretic karyotype (EK) was used to type 13 clinical isolates of Cryptococcus neoformans from eight AIDS patients. All of the isolates were also tested for their in vitro susceptibilities to fluconazole, itraconazole, D0870, flucytosine, and amphotericin B by a broth macrodilution technique performed according to the National Committee for Clinical Laboratory Standards recommendations. Although all strains were isolated from a limited geographic area, DNA typing showed a wide genetic variation in this group of patients, yielding seven different patterns. Two patients in whom C. neoformans was isolated in the same time period shared similar EK profiles, suggesting the possibility of cross-infection. In three patients, sequential isolates were evaluated: in two of them, EK analysis showed the persistence of the same genotype throughout the infection, whereas from the third, two isolates of C. neoformans with two different DNA profiles were obtained. Despite the small number of strains considered in this study, our susceptibility data indicate that C. neoformans isolates are very susceptible to the new triazoles.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

[Detection of capsular polysaccharide antigen of Cryptococcus neoformans in patients with AIDS and neurocryptococcosis in São Paulo, Brazil].

Capsular polysaccharide antigen (AgPC) of Cryptococcus neoformans was detected by latex agglutination technique (LA) in cerebrospinal fluid and serum of patients with AIDS during their first central nervous system manifestation of the disease. Direct mycological examination and culture were used as controls. Sensitivity was 100% by LA allowing an early specific treatment of cryptococcosis. Initial titres of AgPC in such patients can be > 1000000 and it appears that when such titres are present in the serum they are related to mortality during treatment. Surviving patients showed positivity of the direct mycological examination and AgPC of C. neoformans in cerebrospinal fluid and sera even after treatment and clinical recovery.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans.

The development of T cell immunity is required to clear a pulmonary Cryptococcus neoformans infection (via the recruitment and activation of inflammatory cells). The objective of our studies was to determine whether TNF-alpha is required during the afferent phase of the response. The levels of TNF-alpha mRNA and protein in the lungs increased following intratracheal inoculation of CBA/J mice with C. neoformans 52 and preceded the development of an inflammatory response in the lungs. Administration of neutralizing TNF-alpha-specific antiserum on days 0, 3, 6, and 9 reduced inflammatory cell recruitment by 80% on day 13, resulting in a 3-fold increase in lung C. neoformans CFU. The number of CD4+ T cells was decreased by 65%, the number of neutrophils was decreased by 84%, and the number of macrophages was decreased by >98%. Strikingly, a single dose of neutralizing anti-TNF-alpha serum was sufficient to prevent the development of protective cell-mediated immunity on day 35 if administered on day 0, but was ineffective if delayed until day 14. Day 0 anti-TNF-alpha-treated mice could not generate cryptococcus-specific delayed type hypersensitivity reactivity, clear the infection from their lungs (10(4)-fold increase in CFU), control dissemination to the spleen and brain (10(5)- and 10(6)-fold increases in CFU), or adoptively transfer cryptococcus-specific immunity (mononuclear cell recruitment into the lungs following intratracheal challenge or footpad delayed type hypersensitivity). Thus, the production of TNF-alpha during the afferent phase of the immune response against a pulmonary C. neoformans infection (before day 14) is critical for the development of protective T cell immunity in both the lungs and extrapulmonary sites.

Animals↗
PubMed1984

Effects of diethylstilbestrol and cyclophosphamide on the pathogenesis of experimental Cryptococcus neoformans infections.

Treatment of mice with a single dose of cyclophosphamide 24 h before challenge with Cryptococcus neoformans increased host survival, whereas treatment with 10 daily exposures of cyclophosphamide, starting 2 days before challenge, markedly reduced survival in mice challenged on the second day of drug treatment. Treatment with 14 daily exposures of diethylstilbestrol before challenge with C. neoformans did not markedly affect host survival. A correlation was sought between the distribution of radiolabeled C. neoformans and host survival. Radiolabeled C. neoformans administered intravenously was cleared rapidly from the blood of naive mice and accumulated in the lungs, liver and kidney within 1 h. The radiolabeled yeasts were subsequently cleared from the lungs. The distribution of radiolabeled C. neoformans among organs was generally the same in control mice and mice treated with diethylstilbestrol of various cyclophosphamide regimens after 3 or 24 h. The distribution of C. neoformans measured as colony forming units was generally in agreement with results from radioactivity measurements for animals sacrificed 3 or 24 h after challenge. One week after challenge, C. neoformans colonies were grown from the brain, liver and kidneys. C. neoformans was found in the brain within 1 h after i.v. challenge, suggesting that the central nervous system disease in mice challenged i.v. resulted from a primary infection of the brain.

Animals↗
PubMed1998

Role of the capsule in microglial cell-Cryptococcus neoformans interaction: impairment of antifungal activity but not of secretory functions.

Using two isogenic strains of Cryptococcus neoformans, we studied the influence of the capsule in C. neoformans microglial-cell interaction. We demonstrate that the acapsular mutant yeasts (CAP67) are more susceptible to phagocytosis and killing than encapsulated yeasts (B3501) by the murine microglial cells, BV-2. RT-PCR analysis showed that the pattern of gene transcripts for tumour necrosis factor alpha (TNF-a), interleukin (IL)-1beta, IL-6, IL-12p40 and granulocyte macrophage colony stimulating factor remains unchanged following BV-2 cell infection with CAP67 or B3501 yeasts. Moreover, no induction of TNF-alpha secretion occurs in BV-2 cells infected with either B3501 or CAP67 yeasts or exposed to glucuronoxylomannan (GXM) or galactoxylomannan (GalXM). Nevertheless, lipopolysaccharide-induced TNF-alpha secretion is downregulated by cell infection with B3501 or CAP67 yeasts or exposure to GXM or GalXM. Overall, by means of a continuous cell line, it appears that the C. neoformans capsule is detrimental to microglial cell antifungal activity, while no effect can be attributed to the capsule as trend of cytokine gene expression and TNF-alpha secretion.

Animals↗
PubMed2000

Phagocytosis and protein processing are required for presentation of Cryptococcus neoformans mitogen to T lymphocytes.

In addition to eliciting antigen specific T-cell-mediated immunity, Cryptococcus neoformans possesses a mitogen (CnM) that activates naive T cells to proliferate. This mechanism of T-cell activation is accessory cell dependent and major histocompatibility complex unrestricted. CnM-induced T-cell proliferation correlates with internalization of the organism, suggesting that intracellular processing is required to liberate CnM prior to presentation to T cells. To determine whether phagocytosis and processing are required, various inhibitors of accessory cell uptake and processing were used. C. neoformans was observed within the accessory cells. Paraformaldehyde fixation of the accessory cell abrogated presentation of CnM to T cells, indicating that a dynamic accessory cell surface was required. A lysosomotropic agent abrogated the response to CnM but had no effect on a control stimulus that did not require processing. Both aspartic acid and cysteine protease inhibitors blocked effective processing of CnM, so that it was unable to stimulate T cells. Finally, an inhibitor of microfilament polymerization abrogated proliferation to CnM. These results indicate that the mitogenic activity of C. neoformans requires phagocytosis of the organism, lysosomal or endosomal processing, proteolytic activity, and microfilament polymerization and intracellular transport as a prerequisite for T-cell proliferation.

Actin Cytoskeleton↗
PubMed1993

Direct interactions of human lymphocytes with the yeast-like organism, Cryptococcus neoformans.

Lymphocytes, especially CD4+ T cells, are essential for clearance of the yeast-like organism Cryptococcus neoformans from the infected host. The mechanism(s) by which the lymphocytes facilitate elimination of cryptococci has not been elucidated. It is generally thought, however, that lymphocytes reactive with C. neoformans indirectly function by production of lymphokines to enhance clearance of the organism by natural effector cells such as macrophages. In the present study, we assessed the ability of freshly isolated human lymphocytes to interact directly with C. neoformans and to limit the growth of the organism in vitro. We found that large granular lymphocytes (LGL) as well as T cells bound to cryptococcal cells when the lymphocytes were mixed with the cryptococcal cells at a 2:1 ratio. The physical binding interactions of the two lymphocyte populations were different. LGL attached to the cryptococcal cells by many microvilli; T lymphocytes associated with the yeast through broad areas of membrane attached to the cryptococcal cell surface. The two types of lymphocyte interactions did not result in phagocytosis but resulted in direct inhibition of cryptococcal growth, making these lymphocyte interactions with cryptococci distinctly different from interactions of monocytes with cryptococci. With the human natural killer (NK) cell line, NK 3.3, we confirmed that NK cells that were present in the LGL population were capable of limiting the growth of C. neoformans. Through immunoelectron microscopy, human CD3+ lymphocytes were seen attached to cryptococcal cells and by mass cytolysis, human CD3+ lymphocytes were shown to be responsible for inhibition of C. neoformans growth. The direct inhibitory interactions of NK cells and T lymphocytes with cryptococcal cells may be important means of host defense against this ubiquitous organism that frequently causes life-threatening disease in AIDS patients.

CD3 Complex↗
PubMed1997

Epitope location in the Cryptococcus neoformans capsule is a determinant of antibody efficacy.

Monoclonal antibodies (mAbs) to the polysaccharide capsule of Cryptococcus neoformans can prolong survival in mice. However, the properties of antibodies that mediate protection are not fully understood. The IgM mAbs 12A1 and 13F1 originated from the same B cell and differ only by somatic mutations in their variable regions; yet mAb 12A1 protects against serotype D infection, while mAb 13F1 does not. Phage peptide display libraries were used to analyze the fine specificity of these two mAbs. The selection of distinct peptide motifs from identical libraries confirmed that mAbs 12A1 and 13F1 bound to two distinct epitopes. Immunofluorescence and immunoelectron microscopy studies revealed differences in antibody localization within the capsule of serotype D strain; mAb 12A1 bound to the outer rim of the capsule resulting in an annular pattern, whereas mAb 13F1 bound throughout the capsule and had a punctate appearance. The difference in the binding pattern of mAb 12A1 and 13F1 was not observed on serotype A organisms, where both mAbs bound to the capsule with an annular fluorescence pattern. The fluorescence pattern of binding correlated with protective efficacy; mAb 13F1 prolonged survival of mice infected with the J11 serotype A strain (annular fluorescence), but not serotype D strains (punctate pattern). Annular binding, but not punctate binding, was associated with increased opsonic efficacy for phagocytosis of C. neoformans by J774.16 macrophage-like cells. The correlation between capsular binding pattern, opsonic activity, and ability to prolong survival suggests that the efficacy of anticryptococcal antibodies is dependent upon where they bind in the polysaccharide capsule.

Animals↗
PubMed2002

[IWhich are the conditions for Cryptococcus neoformans var. neoformans-strains from avian excrements as a cause for human infections?].

Detection of antigen factors of Cryptococcus with factor sera in slide agglutination confirms diagnosis of species and varieties of Cryptococcus neoformans (Cr. n). This method is important in investigations of sources of infections. Serotype D strains of Cr. neoformans were detected in pigeon breedings from Thuringia exclusively. Because of that an essential difference exists in comparison to human isolates in Germany and strains from breeding stocks of companion birds in Thuringia where serotype A strains are predominant in pet birds and in human infections. Using different primers in PCR fingerprinting Cr. neoformans isolates can be assigned to serotypes A, B, C and D and to varieties Cr. neoformans neoformans and Cr. neoformans gattii (primer FM 1). On the other hand, genetic heterogeneity of Cr. neoformans strains is detectable within the serotypes A and D (primer 60-26). This genetic heterogeneity can be demonstrated in investigations by Fourier Transform Infrared (FTIR) spectroscopy, too. Isolated Cr. neoformans strains from pigeons (serotype D) could be divided into 3 and from pet birds (serotype A) into 2 different clusters by FTIR spectroscopy. It is important to take into account heterogeneity of strains within serotypes for determination of infection chains of human disease.

Animals↗
PubMed1967

Micromorphology of Cryptococcus neoformans.

Fine details of the internal and external morphology of Cryptococcus neoformans as seen in ultrathin sections are described and illustrated with electron micrographs. The capsule characteristic of this species contained microfibrils (30 to 40 A in diameter) that appeared to radiate from the cell wall and to coil and intertwine in various directions. These thin, uniformly structured, electron-dense filaments are believed to represent complex polysaccharide molecules. The internal morphology of C. neoformans was in many ways similar to that of yeasts studied by other authors. The cell was uninucleate with a single nucleolus. The nuclear envelope, a pair of unit membranes interrupted by pores, was typical of that found in eucaryotic organisms. Smooth endoplasmic reticulum, mitochondria, vacuoles, storage granules, and ribosomes were consistent features of the cytoplasm. In addition, C. neoformans presented membranous organelles derived from the plasma membrane and comparable to bacterial mesosomes and mitochondria of an annulate type.

Cell Wall↗