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PubMed1996

Karyotype instability in Cryptococcus neoformans infection.

The electrophoretic karyotypes of 32 clinical and 3 environmental Cryptococcus neoformans isolates from New York City were studied by contour clamped homogeneous electrophoresis. There was extensive variation among the electrophoretic karyotypes of isolates from different patients. Sequential C. neoformans isolates from patients with chronic or relapsing infection had very similar karyotypes. However, minor differences in electrophoretic karyotypes were detected among sequential isolates from 50% of the patients studied, suggesting the occurrence of chromosomal rearrangements or deletions in vivo. This hypothesis was tested by infecting mice, recovering isolates from mouse organs, and comparing the electrophoretic karyotypes before and after passage. Three clinical and three environmental strains were studied before and after passage in mice. Karyotype differences were detected after mouse passage for one clinical and two environmental strains. Our results indicate (i) extensive karyotype variation among isolates from a small geographic regions, (ii) a high frequency of electrophoretic karyotype differences among sequential isolates from individual patients, and (iii) the occurrence of electrophoretic karyotype changes during experimental infection of mice. The implications of these observations are discussed.

AIDS-Related Opportunistic Infections↗
PubMed1993

Cryptococcus neoformans var. gattii in India.

An examination of 18 clinical isolates of Cryptococcus neoformans from India revealed that 15 belonged to C. neoformans var. neoformans (serotype A = 13 isolates, serotype AD = two isolates) and three belonged to C. neoformans var. gattii (serotype B). This is the first documented record of the var. gattii and serotype AD of the var. neoformans occurring in India.

Cryptococcosis↗
PubMed1999

Laccase protects Cryptococcus neoformans from antifungal activity of alveolar macrophages.

While laccase of Cryptococcus neoformans is implicated in the virulence of the organism, our recent studies showing absence of melanin in the infected mouse brain has led us to a search for alternative roles for laccase in cryptococcosis. We investigated the role of laccase in protection of C. neoformans against murine alveolar macrophage (AM)-mediated antifungal activity by using a pair of congenic laccase-positive (2E-TUC) and laccase-deficient (2E-TU) strains. The laccase-positive cells with laccase derepression were more resistant to the antifungal activity of AM than a laccase-deficient strain ([28.9 +/- 1.2]% versus [40.2 +/- 2.6]% killing). Addition of L-dopa to Cryptococcus to produce melanin in a laccase-positive strain resulted in a slight increase in protection of C. neoformans from the antifungal activity of macrophages ([25.4 +/- 3.4]% versus [28.9 +/- 1.2]% killing). Recombinant cryptococcal laccase exhibited iron oxidase activity in converting Fe(II) to Fe(III). Moreover, recombinant laccase inhibited killing of C. neoformans by hydroxyl radicals catalyzed by iron in a cell-free system. Addition of the hydroxyl radical scavenger mannitol or dimethyl sulfoxide to AMs prior to the introduction of cryptococcal cells decreased killing of both strains and reduced the difference in susceptibility between the laccase-positive and laccase-deficient strains. Furthermore, laccase-mediated protection from AM killing was inhibited by the addition of Fe(II), presumably by overcoming the effects of the iron oxidase activity of cryptococcal laccase. These results suggest that the iron oxidase activity of laccase may protect C. neoformans from macrophages by oxidation of phagosomal iron to Fe(III) with a resultant decrease in hydroxyl radical formation.

Animals↗
PubMed2005

Mitochondrial functioning of constitutive iron uptake mutations in Cryptococcus neoformans.

Randomly obtained, constitutive plasma membrane ferric reductase/ferrous uptake mutants of Cryptococcus neoformans were mapped to four distinct loci by meiotic analysis. One of those loci, FRR1 , was previously found homologous to MRS3 and MRS4 of Saccharomyces cerevisiae , which determine proteins involved in mitochondrial transport of iron. We were able to complement, clone, sequence and thereby identify two of the three remaining constitutive uptake loci. FRR3 was found to be homologous to ISU1 and ISU2 of S. cerevisiae, which form mitochondrial iron-sulfur complexes; FRR4 was found to be homologous to YFH1, the yeast frataxin homologue, which also participates in iron-sulfur cluster biogenesis. Because of the constitutive iron uptake seen in these mutants, mitochondria appear to have a central role in the cellular iron economy; moreover, as judged by our mutational statistics, the genetic machinery for mitochondrial iron accumulation may be more complex than that of the cytoplasm.

Amino Acid Sequence↗
PubMedDate not supplied

[Cryptococcus neoformans chemotyping. Review of the literature. New epidemiologic data on cryptococcosis. Our experience with the use of C.G.B. media in the study of this yeast].

The purpose of this work was to collect the main information from the literature about the biotyping of Cryptococcus neoformans. The more up-to date research concerning the epidemiology of cryptococcosis comprising quite a few articles, mainly after the advent of AIDS, was also reviewed. The Cryptococcus neoformans varieties neoformans and gattii are well defined biochemically nowadays chiefly through the C.G.B. medium, according to Kwon-Chung et al. (1982). The isolation of C. neoformans var. gattii from flowers and leaves of Eucalyptus camaldulensis and Eucalyptus tereticornis, specially in Australia, through the works of Ellis & Pfeiffer (1990) and Pfeiffer & Ellis (1992) permitted very interesting epidemiological investigations on C. neoformans, a capsulated yeast by which Sanfelice, in Italy (1894; 1895) attracted attention of medical class. Busse, in 1894, described the first human case of cryptococcosis under the presentation of a bone lesion simulating sarcoma. In this paper, the Brazilian researchers focused on this subject were pointed out, followed by the Author's experience with the C.G.B. medium (L-canavanine, glycine and bromothymol blue) proposed by Kwon-Chung et al. (1982) with very good results. It was possible with such medium the study of 50 C.N.S. liquor samples, being 39 from AIDS patients (78%) and 11 from non-AIDS ones (22%). Thirty-seven out of the 39 HIV-positive patients (74%) were identified as C. neoformans var. gattii. From the negative HIV, 8 (16%) were classified as C. neoformans var. neoformans and 3 (6%) as C. neoformans var. gattii. We could not perform the serotyping of the above referred samples. It is evident anyway that in Brazil there exist both varieties gattii and neoformans, agents of neurocryptococcosis, including AIDS patients. The importance of neurocryptococcosis, mainly among AIDS patients, is stressed here, showing once more the value of C.G.B. medium in the typing of C. neoformans in its two varieties. Also, it is of relevant importance the demonstration that some species of eucalyptus may act as "host-trees" of C. neoformans var. gattii.

Animals↗
PubMed2003

Recapitulation of the sexual cycle of the primary fungal pathogen Cryptococcus neoformans var. gattii: implications for an outbreak on Vancouver Island, Canada.

Cryptococcus neoformans is a human fungal pathogen that exists as three distinct varieties or sibling species: the predominantly opportunistic pathogens C. neoformans var. neoformans (serotype D) and C. neoformans var. grubii (serotype A) and the primary pathogen C. neoformans var. gattii (serotypes B and C). While serotypes A and D are cosmopolitan, serotypes B and C are typically restricted to tropical regions. However, serotype B isolates of C. neoformans var. gattii have recently caused an outbreak on Vancouver Island in Canada, highlighting the threat of this fungus and its capacity to infect immunocompetent individuals. Here we report a large-scale analysis of the mating abilities of serotype B and C isolates from diverse sources and identify unusual strains that mate robustly and are suitable for further genetic analysis. Unlike most isolates, which are of both the a and alpha mating types but are predominantly sterile, the majority of the Vancouver outbreak strains are exclusively of the alpha mating type and the majority are fertile. In an effort to enhance mating of these isolates, we identified and disrupted the CRG1 gene encoding the GTPase-activating protein involved in attenuating pheromone response. crg1 mutations dramatically increased mating efficiency and enabled mating with otherwise sterile isolates. Our studies provide a genetic and molecular foundation for further studies of this primary pathogen and reveal that the Vancouver Island outbreak may be attributable to a recent recombination event.

Biolistics↗
PubMed2000

Human neutrophil-mediated nonoxidative antifungal activity against Cryptococcus neoformans.

It has long been appreciated that polymorphonuclear leukocytes (PMN) kill Cryptococcus neoformans, at least in part via generation of fungicidal oxidants. The aim of this study was to examine the contribution of nonoxidative mechanisms to the inhibition and killing of C. neoformans. Treatment of human PMN with inhibitors and scavengers of respiratory burst oxidants only partially reversed anticryptococcal activity, suggesting that both oxidative and nonoxidative mechanisms were operative. To define the mediators of nonoxidative anticryptococcal activity, PMN were fractionated into cytoplasmic, primary (azurophil) granule, and secondary (specific) granule fractions. Incubation of C. neoformans with these fractions for 18 h resulted in percent inhibition of growth of 67.4 +/- 3.4, 84.6 +/- 4.4, and 29.2 +/- 10.5 (mean +/- standard error, n = 3), respectively. Anticryptococcal activity of the cytoplasmic fraction was abrogated by zinc and depletion of calprotectin. Antifungal activity of the primary granules was significantly reduced by pronase treatment, boiling, high ionic strength, and magnesium but not calcium. Fractionation of the primary granules by reverse phase high-pressure liquid chromatography on a C(4) column over an acetonitrile gradient revealed multiple peaks with anticryptococcal activity. Of these, peaks 1 and 6 had substantial fungistatic and fungicidal activity. Peak 1 was identified by acid-urea polyacrylamide gel electrophoresis (PAGE) and mass spectroscopy as human neutrophil proteins (defensins) 1 to 3. Analysis of peak 6 by sodium dodecyl sulfate-PAGE revealed multiple bands. Thus, human PMN have nonoxidative anticryptococcal activity residing principally in their cytoplasmic and primary granule fractions. Calprotectin mediates the cytoplasmic activity, whereas multiple proteins, including defensins, are responsible for activity of the primary granules.

Blood Bactericidal Activity↗
PubMed1998

A novel quantitative mating assay for the fungal pathogen Cryptococcus neoformans provides insight into signalling pathways responding to nutrients and temperature.

Cryptococcus neoformans is a fungal pathogen that causes a lethal meningitis in immunocompromised individuals. Several factors are associated with virulence of this fungus, including its mating type; however, the mechanism by which mating type affects virulence is unknown. C. neoformans is a basidiomycete that exists in two mating types called a and alpha that can fuse to form an a/alpha dikaryon. A mating assay was developed that allowed a quantitative analysis of cryptococcal mating physiology. Interestingly, the efficiency of mating appeared to be dependent on temperature, being highest at 30 degrees C and almost completely absent at 37 degrees C. Thus, while mating type itself may be associated with virulence (which must occur at 37 degrees C), the ability to mate is probably not a virulence factor. Mating efficiency was increased by altering the carbon or nitrogen sources to give so-called starvation media. The addition of various drugs also seemed to alter the frequency of mating, depending on the composition of mating medium. The data suggested that cAMP, 8-bromo-cAMP and caffeine increased mating on starvation medium but only cAMP and 8-bromo-cAMP stimulated mating on rich medium; caffeine was unable to stimulate mating on rich medium. Aluminium fluoride, an activator of heterotrimeric GTP-binding proteins (G-proteins), was also found to stimulate mating, suggesting the involvement of a G-protein that may regulate the level of cAMP.

Cryptococcus neoformans↗
PubMed1989

Characterization of Cryptococcus neoformans capsular glucuronoxylomannan polysaccharide with monoclonal antibodies.

Mice were immunized with Cryptococcus neoformans serotype A capsular glucuronoxylomannan (GXM) conjugated to bovine serum albumin-adipic dihydrazide. Two splenocyte fusions yielded two monoclonal antibodies (MAbs) that were highly reactive in dot enzyme immunoassay, immunofluorescence, and sandwich enzyme immunoassay. The first MAb, BD-1 [immunoglobulin G1 (kappa) [IgG1(kappa)]], was GXM-A and GXM-D specific, whereas the second MAb, BA-4 (IgM), reacted with GXM-A and GXM-B. A third MAb, CD-6 [IgG1(kappa)], originated from mice immunized with O-deacetylated GXM-C-bovine serum albumin and reacted with GXMs of all four serotypes. Two of the MAbs (CD-6 and BD-1) were further characterized with chemically modified GXMs. Removal of glucuronosyl residues completely inhibited the binding of both MAbs, implicating (1----2)-beta-glucuronic acid as a key component of the epitope. Removal of (1----2)-beta-xylosyl residues decreased reactivity to an intermediate extent. O deacetylation led to a measurable decrease but had the least inhibitory effect of the three GXM derivatives tested. The combining site for these two MAbs appears to be a complex antigenic determinant involving more than one glycosidic residue.

Antibodies, Fungal↗
PubMed2003

Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and alpha isolates.

Cryptococcus neoformans is a human-pathogenic fungus that has evolved into three distinct varieties that infect most prominently the central nervous system. A sexual cycle involving haploid cells of a and alpha mating types has been reported for two varieties (C. neoformans var. neoformans, serotype D, and C. neoformans var. gattii, serotypes B and C), yet the vast majority of infections involve a distinct variety (C. neoformans var. grubii, serotype A) that has been thought to be clonal and restricted to the alpha mating type. We recently identified the first serotype A isolate of the a mating type which had been thought to be extinct (strain 125.91). Here we report that this unusual strain can mate with a subset of pathogenic serotype A strains to produce a filamentous dikaryon with fused clamp connections, basidia, and viable recombinant basidiospores. One meiotic segregant mated poorly with the serotype A reference strain H99 but robustly with a crg1 mutant that lacks a regulator of G protein signaling and is hyperresponsive to mating pheromone. This meiotic segregant was used to create congenic a and alpha mating type serotype A strains. Virulence tests with rabbit and murine models of cryptococcal meningitis showed that the serotype A congenic a and alpha mating type strains had equivalent virulence in animal models, in contrast to previous studies linking the alpha mating type to increased virulence in congenic serotype D strains. Our studies highlight a role for sexual recombination in the evolution of a human fungal pathogen and provide a robust genetic platform to establish the molecular determinants of virulence.

Animals↗
PubMed1994

Comparisons between in vitro glial cell adherence and internalization of non-encapsulated and encapsulated strains of Cryptococcus neoformans.

The adherence of non-encapsulated and encapsulated strains of Cryptococcus neoformans to rat glial cells in culture was compared. Like the encapsulated strain, the adherence of the unencapsulated strain was affected by the yeast culture age and growth temperature. Yeasts grown to late stationary phase at 37 degrees C were the most adherent. Neither encapsulated nor non-encapsulated strains adhered to glial monolayers when the experiments were conducted at 5 degrees C, indicating that metabolically active mammalian cells were required for yeast adherence. Additionally, the non-encapsulated strain was consistently three times more adherent than the encapsulated strain, suggesting that the non-encapsulated strain either had more adhesins or more adhesins were exposed. Electron microscope studies indicated that both strains were internalized by glial cells, an event previously not reported for this mammalian cell type. The same carbohydrates (N-acetyl-D-glucosamine, sucrose and inositol) that inhibited adherence of the encapsulated strain the most, also inhibited adherence of the non-encapsulated strain, again indicating similar adhesin mechanisms. Both encapsulated and non-encapsulated strains were made non-adherent by treatment with pronase, papain, trypsin and amylase. Immobilized amylase appeared to remove an adhesin fragment that bound to glial cells and inhibited the adherence of intact cryptococci.

Amylases↗
PubMed1990

Comparative morphological and biological studies on the itraconazole- and ketoconazole-resistant mutants of Cryptococcus neoformans.

Studies were carried out on the resistance in vitro of Cryptococcus neoformans to the oral antifungal drugs itraconazole and ketoconazole. None of the six sensitive strains tested developed resistance to itraconazole or ketoconazole by serial transfer on Sabouraud's glucose agar plates containing increasing concentrations of either drug. One mutant resistant to itraconazole, and one mutant resistant to ketoconazole, were isolated from the progenies of yeast cells surviving after treatment with a mutagenic substance, N-methyl-N'-nitro-N-nitroso-guanidine. These mutants were capable of growing in the presence of high concentrations of the drugs to which they were resistant. The itraconazole- and ketoconazole-resistant mutants obtained by mutagenesis were compared morphologically and biologically. The itraconazole-resistant mutant was characterized by the formation of very rough colonies which varied in size and shape, production of a large number of cell clusters, complete loss of capsule formation, and major degenerative changes in the cells, while in the ketoconazole-resistant mutant these changes were less pronounced and no cell clusters were formed. The acquisition of resistance was more stable in the itraconazole-resistant mutant than in the ketoconazole-resistant mutant. Both mutants showed partial cross-resistance and complete loss of virulence for mice.

Animals↗
PubMed1986

Ultrastructure of acapsular mutant Cryptococcus neoformans cap 67 and monosaccharide composition of cell extracts.

Acapsular mutant Cryptococcus neoformans cap 67 was grown in Pine's citrate broth medium for 3 days and the cells then transferred to a nitrogen-free medium for 6 days. The cells were subjected to a four stage extraction with buffered Triton-X100, cold dilute alkaline borohydride, hot dilute acetic acid, and a second alkaline extraction. Galactoxylomannan antigens were recovered from the culture supernates of both 3 day-old and 9 day-old yeast cells. The alkaline extracts contained water-soluble galactoxylomannan and a water-insoluble glucan. Dilute acid treatment released a minor amount of carbohydrate from the cells. The second alkaline extraction yielded increased amounts of glucan and galactoxylomannan from the 9 day-old cells. Soluble non-dialyzable cell extracts were antigenically identical in immunodiffusion with the culture supernate antigens. After the extraction sequence, all of the galactose, xylose, and mannose were removed from the cells. The walls retained their shape after extraction but their layers were loosened. Cells resuspended in nitrogen-free medium for six days developed thickened walls with alternating electron-dense and electron-lucent layers. The major constituent of the thickened 9 day-old cell walls was glucose, only 5% glucosamine was detected.

Antigens, Fungal↗
PubMed2003

Characterization of Cu,Zn superoxide dismutase (SOD1) gene knock-out mutant of Cryptococcus neoformans var. gattii: role in biology and virulence.

The pathogenic yeast Cryptococcus neoformans (Cn) var. gattii causes meningoencephalitis in healthy individuals, unlike the better known Cn varieties grubii and neoformans, which are common in immunocompromised individuals. The virulence determinants and mechanisms of host predilection are poorly defined for var. gattii. The present study focused on the characterization of a Cu,Zn superoxide dismutase (SOD1) gene knock-out mutant constructed by developing a DNA transformation system. The sod1 mutant was highly sensitive to the redox cycling agent menadione, and showed fragmentation of the large vacuole in the cytoplasm, but no other defects were seen in growth, capsule synthesis, mating, sporulation, stationary phase survival or auxotrophies for sulphur-containing amino acids. The sod1 mutant was markedly attenuated in virulence in a mouse model, and it was significantly susceptible to in vitro killing by human neutrophils (PMNs). The deletion of SOD1 also resulted in defects in the expression of a number of virulence factors, i.e. laccase, urease and phospholipase. Complementation of the sod1 mutant with SOD1 resulted in recovery of virulence factor expression and menadione resistance, and in restoration of virulence. Overall, these results suggest that the antioxidant function of Cu,Zn SOD is critical for the pathogenesis of the fungus, but is dispensable in its saprobic life. This report constitutes the first instance in which superoxide dismutase has been directly implicated in the virulence of a fungal pathogen.

Animals↗
PubMed1985

Chemical characterization of capsular polysaccharide from Cryptococcus neoformans serotype A-D.

During a study of serotyping of Cryptococcus neoformans, we found that the type strain of C. neoformans (CBS 132) was serotype A-D. This strain agglutinated with both factor 7 serum (specific for serotype A) and factor 8 serum (specific for serotype D) in our serotyping system. Therefore, we investigated the chemical structure of the antigenic capsular polysaccharide of this strain. The soluble capsular polysaccharide was obtained from the culture supernatant fluid by precipitation with ethanol. Column chromatography of the polysaccharide on DEAE-cellulose yielded three fractions (F-1 to F-3). The major antigenic activity was found in the F-3 fraction. The results obtained by methylation analysis, controlled Smith degradation-methylation analysis, partial acid hydrolysis, and other structural studies of F-3 polysaccharide indicated that the polysaccharide contains mannose, xylose, and glucuronic acid at a ratio of 7:2:2, and has a backbone of alpha (1-3)-linked D-mannopyranoside residues with a single branch of beta (1-2)-xylose and glucuronic acid. The ratio of mannose residues with or without a branch in the F-3 polysaccharide was 4:3 and its molecular weight calculated from the average of the degree of polymerization was 46,500 daltons. These results indicate that the chemical structure of the capsular polysaccharide of serotype A-D is very similar to those from serotypes A and D, suggesting that small differences in the molar ratio and pattern of linkage of monosaccharides in the branch of the polysaccharides of the three serotypes may be responsible for their different specificities.

Antigens, Bacterial↗
PubMed1992

4-oxatetradecanoic acid is fungicidal for Cryptococcus neoformans and inhibits replication of human immunodeficiency virus I.

Candida albicans and Cryptococcus neoformans are major causes of systemic fungal infections, particularly in patients with acquired immunodeficiency syndrome. Metabolic labeling studies revealed that these organisms synthesize a small number of N-myristoylproteins, the most prominent being 20-kDa ADP-ribosylation factors (Arfs). C. albicans Arf has approximately 80% identity with the essential Arf1 and Arf2 proteins of Saccharomyces cerevisiae. [3H]Myristic acid analogs with oxygen for -CH2- substitutions at C4, C6, C11, and C13 are incorporated into cellular N-myristoylproteins, phospholipids, and neutral lipids produced by these three yeasts during exponential growth at 30 degrees C in complex media. Analog- and organism-specific differences in the efficiency of labeling of proteins and lipid classes were observed. The effects of oxatetradecanoic acids with oxygen for -CH2- substitutions at C3-C13 on C. neoformans, C. albicans, and S. cerevisiae were assessed during mid-log phase growth at 30 degrees C. A single dose of 3-oxa-, 4-oxa-, 5-oxa- or 6-oxatetradecanoic acid (O3-O6, final concentration = 300 microM) was able to inhibit growth of C. neoformans in the order O4 greater than O5 greater than O3 approximately O6. The other compounds were inactive. 4-Oxatetradecanoic acid was fungicidal, producing a 10,000-fold reduction in viable cell number 1 h after administration and continued suppression of cell growth for 7 h. A clear dose response was observed over a concentration range of 100-300 microM. 4-Oxatridecanoic acid was 100-fold less potent in reducing cell viability than 4-oxatetradecanoic acid but more potent than 5-oxatridecanoic acid. O4 produced approximately 10-100-fold reductions in the viability of C. albicans and S. cerevisiae at 300-500 microM, respectively, whereas O5 and O6 were less active. Since N-myristoylation of the Pr55gag polyprotein precursor produced by human immunodeficiency virus I (HIV-I) is essential for its assembly, we also assessed the antiviral effects of 4-oxatetradecanoic acid. O4 is able to produce a 50% reduction in the replication of HIV-I in acutely infected human T-lymphocyte cell lines at a concentration of 18 microM. Together, these data suggest that (i) the position of the oxygen for methylene substitution is a critical determinant of the fungicidal activity of O4 and (ii) NMT may be an attractive therapeutic target for treating opportunistic fungal infections in patients infected with HIV-I.

ADP-Ribosylation Factor 1↗
PubMed2002

Differences in components at delayed-type hypersensitivity reaction sites in mice immunized with either a protective or a nonprotective immunogen of Cryptococcus neoformans.

Cell-mediated immunity is the major protective mechanism against Cryptococcus neoformans. Delayed swelling reactions, i.e., delayed-type hypersensitivity (DTH), in response to an intradermal injection of specific antigen are used as a means of detecting a cell-mediated immune (CMI) response to the antigen. We have found previously that the presence of an anticryptococcal DTH response in mice is not always indicative of protection against a cryptococcal infection. Using one immunogen that induces a protective anticryptococcal CMI response and one that induces a nonprotective response, we have shown that mice immunized with the protective immunogen undergo a classical DTH response characterized by mononuclear cell and neutrophil infiltrates and the presence of gamma interferon and NO. In contrast, immunization with the nonprotective immunogen results in an influx of primarily neutrophils and production of tumor necrosis factor alpha (TNF-alpha) at the DTH reaction site. Even when the anticryptococcal DTH response was augmented by blocking the down-regulator, CTLA-4 (CD152), on T cells in the mice given the nonprotective immunogen, the main leukocyte population infiltrating the DTH reaction site is the neutrophil. Although TNF-alpha is increased at the DTH reaction site in mice immunized with the nonprotective immunogen, it is unlikely that TNF-alpha activates the neutrophils, because the density of TNF receptors on the neutrophils is reduced below control levels. Uncoupling of DTH reactivity and protection has been demonstrated in other infectious-disease models; however, the mechanisms differ from our model. These findings stress the importance of defining the cascade of events occurring in response to various immunogens and establishing the relationships between protection and DTH reactions.

Animals↗
PubMed1991

Encapsulation of Cryptococcus neoformans impairs antigen-specific T-cell responses.

The encapsulated yeast Cryptococcus neoformans is a significant cause of opportunistic infection in patients with impaired cell-mediated immunity. The major virulence determinant of the organism is an antiphagocytic polysaccharide capsule synthesized after entry into the host. Using both an encapsulated virulent strain and an acapsular avirulent mutant, we have demonstrated the reduced ability of the encapsulated strain to stimulate specific T-cell responses in vitro. This reduction was mediated by the antiphagocytic action of the capsule rather than by direct inhibition of antigen processing and presentation, since prior opsonization with complement enhanced the ingestion of encapsulated yeast cells by purified antigen-presenting cells and allowed significant T-cell activation. Once ingestion had occurred, cryptococci were efficiently processed by activated macrophages via a chloroquine-sensitive pathway. Cryptococcal antigens were available for T-cell recognition within 1 to 2 h of interaction with macrophages and presented in a major histocompatibility complex-restricted manner. Our results suggest that the antiphagocytic action of the polysaccharide capsule is an important determinant for the development of T-cell immunity to C. neoformans.

Animals↗