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PubMed2004

Accumulation of gammadelta T cells in the lungs and their regulatory roles in Th1 response and host defense against pulmonary infection with Cryptococcus neoformans.

The present study was designed to elucidate the role of gammadelta T cells in the host defense against pulmonary infection with Cryptococcus neoformans. The gammadelta T cells in lungs commenced to increase on day 1, reached a peak level on day 3 or 6, and then decreased on day 10 after intratracheal infection. The increase of these cells was similar in monocyte chemoattractant protein (MCP)-1-deficient mice, although that of NK and NKT cells was significantly reduced. The number of live microorganisms in lungs on days 14 and 21 was significantly reduced in mice depleted of gammadelta T cells by a specific mAb compared with mice treated with control IgG. Similarly, elimination of this fungal pathogen was promoted in gammadelta T cell-deficient (TCR-delta(-/-)) mice compared with control littermate mice. Finally, lung and serum levels of IFN-gamma on days 7 and 14 and on day 7 postinfection, respectively, were significantly higher in TCR-delta(-/-) mice than in littermate mice, whereas levels of TGF-beta showed the opposite results. IL-4 and IL-10 were not different between these mice. IFN-gamma production by draining lymph node cells upon restimulation with cryptococcal Ags was significantly higher in the infected TCR-delta(-/-) mice than in control mice. Our results demonstrated that gammadelta T cells accumulated in the lungs in a manner different from NK and NKT cells after cryptococcal infection and played a down-modulatory role in the development of Th1 response and host resistance against this fungal pathogen.

Animals↗
PubMed2004

Unexpected diversity in the fine specificity of monoclonal antibodies that use the same V region gene to glucuronoxylomannan of Cryptococcus neoformans.

Most mAbs to the capsular polysaccharide glucuronoxylomannan (GXM) of Cryptococcus neoformans are generated from the same VH and VL gene families. Prior Ab studies have assessed protective efficacy, Id structure and binding to capsular polysaccharides, and peptide mimetics. These data have been interpreted as indicating that most mAbs to GXM have the same specificity. A new approach to Ab specificity analysis was investigated that uses genetic manipulation to generate C. neoformans variants with structurally different capsules. C. neoformans mutants expressing GXM with defective O-acetylation were isolated and complemented by the C. neoformans gene CAS1, which is necessary for the O-acetylation of GXM. The mAbs exhibited differences in their binding to the GXM from these mutant strains, indicating previously unsuspected differences in specificity. Analysis of three closely related IgMs revealed that one (mAb 12A1) bound to an epitope that did not require O-acetylation, another (mAb 21D2) was inhibited by O-acetylation, and the third (mAb 13F1) recognized an O-acetylation-dependent conformational epitope. Furthermore, an IgG Ab (mAb 18B7) in clinical development retained binding to de-O-acetylated polysaccharide; however, greater binding was observed to O-acetylated GXM. Our findings suggest that microbial genetic techniques can provide a new approach for epitope mapping of polysaccharide-binding Abs and suggest that this method may applicable for studying the antigenic complexity of polysaccharide Ags in other capsulated microorganisms.

Antibodies, Fungal↗
PubMed2005

Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection.

Immunity to the opportunistic fungus Cryptococcus neoformans is dependent on cell-mediated immunity. Individuals with defects in cellular immunity, CD4(+) T cells in particular, are susceptible to infection with this pathogen. In host defense against a number of pathogens, CD8(+) T cell responses are dependent upon CD4(+) T cell help. The goal of these studies was to determine whether CD4(+) T cells are required for the generation of antifungal CD8(+) T cell effectors during pulmonary C. neoformans infection. Using a murine intratracheal infection model, our results demonstrated that CD4(+) T cells were not required for the expansion and trafficking of CD8(+) T cells to the site of infection. CD4(+) T cells were also not required for the generation of IFN-gamma-producing CD8(+) T cell effectors in the lungs. In CD4(-) mice, depletion of CD8(+) T cells resulted in increased intracellular infection of pulmonary macrophages by C. neoformans, increasing the pulmonary burden of the infection. Neutralization of IFN-gamma in CD4(-)CD8(+) mice similarly increased macrophage infection by C. neoformans, thereby blocking the protection provided by CD8(+) T cells. Altogether, these data support the hypothesis that effector CD8(+) T cell function is independent of CD4(+) T cells and that IFN-gamma production from CD8(+) T cells plays a role in controlling C. neoformans by limiting survival of C. neoformans within macrophages.

Animals↗
PubMed2005

Mouse genetic background is a major determinant of isotype-related differences for antibody-mediated protective efficacy against Cryptococcus neoformans.

The protective efficacy of mAbs to Cryptococcus neoformans glucuronoxylomannan depends on Ab isotype. Previous studies in A/JCr and C57BL/6J mice showed relative protective efficacy of IgG1, IgG2a >> IgG3. However, we now report that in C57BL/6J x 129/Sv mice, IgG3 is protective while IgG1 is not protective, with neither isotype being protective in 129/Sv mice. IgG1, IgG2a, and IgG3 had different effects on IFN-gamma expression in infected C57BL/6J x 129/Sv mice. IgG1-treated C57BL/6J x 129/Sv mice had significantly more pulmonary eosinophilia than IgG2a- and IgG3-treated C57BL/6J x 129/Sv mice. C. neoformans infection and Ab administration had different effects on FcgammaRI, FcgammaRII, and FcgammaRIII expression in C57BL/6J, 129/Sv, and C57BL/6J x 129/Sv mice. Our results indicate that the relative efficacy of Ab isotype function against C. neoformans is a function of the genetic background of the host and that IgG3-mediated protection in C57BL/6J x 129/Sv mice was associated with lower levels of IFN-gamma and fewer pulmonary eosinophils. The dependence of isotype efficacy on host genetics underscores a previously unsuspected complex relationship between the cellular and humoral arms of the adaptive immune response.

Animals↗
PubMed2005

Cryptococcus neoformans capsular glucuronoxylomannan induces expression of fas ligand in macrophages.

The major component of capsular material of Cryptococcus neoformans is glucuronoxylomannnan (GXM), a polysaccharide that exhibits potent immunosuppressive properties in vitro and in vivo. The results reported here show that 1) soluble purified GXM induces a prompt, long-lasting, and potent up-regulation of Fas ligand (FasL) on macrophages, 2) the up-regulation of FasL is related to induced synthesis and increased mobilization to the cellular surface, 3) this effect is largely mediated by interaction between GXM and TLR4, 4) FasL up-regulation occurs exclusively in GXM-loaded macrophages, 5) macrophages that show up-regulation of FasL induce apoptosis of activated T cells expressing Fas and Jurkat cells that constitutively express Fas, and 6) anti-Fas Abs rescue T cells from apoptosis induced by GXM. Collectively our results reveal novel aspects of the immunoregulatory properties of GXM and suggest that this nontoxic soluble compound could be used to dampen the immune response, to promote or accelerate the death receptor, and to fix FasL expression in a TLR/ligand-dependent manner. In the present study, we delineate potential new therapeutic applications for GXM that exploit death receptors as key molecular targets in regulating cell-mediated cytotoxicity, immune homeostasis, and the immunopathology of diseases.

Apoptosis↗
PubMed2006

Cryptococcus neoformans glycoantigens are captured by multiple lectin receptors and presented by dendritic cells.

Cell-mediated immune responses to glycoantigens have been largely uncharacterized. Protective T cell responses to the pathogenic yeast Cryptococcus neoformans are dependent on heavily mannosylated Ags termed mannoproteins. In the work presented, the innate immune response to mannoprotein was determined. Purified murine splenic dendritic cells (DC), B cells, and macrophages were used to stimulate mannoprotein-specific T cells. Only DC were capable of any measurable stimulation. Depletion of DC resulted in the abrogation of the T cell response. Human and murine DC rapidly captured fluorescent-labeled mannoprotein by a mannose receptor-mediated process. Using transfected cell lines, the type II C-type lectin receptor DC-specific ICAM-3-grabbing nonintegrin (CD209) was determined to have affinity for mannoprotein. Taken together with prior work demonstrating that mannoprotein was captured by the macrophage mannose receptor (CD206), these data suggest that multiple mannose receptors on DC recognize mannoprotein. Pulsing experiments demonstrated that DC captured sufficient mannoprotein over 2 h to account for 50% of total stimulation. Capture appeared dependent on mannose receptors, as competitive mannosylated inhibitors and calcium chelators each interfered with T cell stimulation. By confocal microscopy, intracellular mannoprotein trafficked to an endo-lysosomal compartment in DC, and at later time points extended into tubules in a similar fashion to the degradation marker DQ-OVA. Mannoprotein colocalized intracellularly with CD206 and CD209. These data suggest that DC provide the crucial link between innate and adaptive immune responses to C. neoformans via a process that is dependent upon the efficient uptake of mannoprotein by mannose receptors.

Animals↗
PubMed2006

Immunologic homeostasis during infection: coexistence of strong pulmonary cell-mediated immunity to secondary Cryptococcus neoformans infection while the primary infection still persists at low levels in the lungs.

Maintenance of immunity to persistent pathogens is poorly understood. In this study, we used a murine model of persistent pulmonary fungal infection to study the ongoing cell-mediated immune response. CBA/J mice with low-level persistent Cryptococcus neoformans infection had CD4+ T cells of effector memory phenotype present in their lungs. Although unable to eliminate the primary infection to sterility, these mice displayed hallmarks of immunologic memory in response to rechallenge with C. neoformans: 1) the secondary cryptococcal challenge was controlled much more rapidly, 2) the inflammatory response developed and resolved more rapidly, 3) CD4+ T and CD8+ T cell responses were higher in magnitude, and 4) effector cytokine production by T cells was greatly enhanced. Depletion of CD4+ T cells at the time of secondary challenge adversely affected clearance of C. neoformans from the lungs. These results demonstrate that persistent low-level infection with C. neoformans does not impair the cell-mediated response to the fungus. Although they are relatively free of overt disease, these mice can respond with a rapid secondary immune response if the burden of C. neoformans increases. These data support the concept that immunologically healthy individuals can maintain low numbers of cryptococci that can become a nidus for re-activation disease during immunodeficient states such as AIDS.

Animals↗
PubMed2006

[Cryptococcus neoformans arthritis in elderly adult: case report and review].

Cryptococcal infection is not frequent in immunocompetent patients. The most commonly involved sites are the lungs and the central nervous system. Cryptococcal osteomyelitis occurs in 5-10% of patients with disseminated cryptococcosis with few reports of cryptococcal arthritis in elderly adults. We describe the case of a 92-year-old woman with a Cryptococcus neoformans knee joint infection associated to osteomyelitis.

Aged↗
PubMed1989

Persistent Cryptococcus neoformans infection of the prostate after successful treatment of meningitis. California Collaborative Treatment Group.

STUDY OBJECTIVE: To assess the frequency of persistent Cryptococcus neoformans infection in patients with the acquired immunodeficiency syndrome (AIDS) after receiving apparently adequate treatment for meningitis. DESIGN: Blood, urine, and cerebrospinal fluid were cultured at the conclusion of primary therapy to assess the adequacy of treatment. SETTING: Outpatient clinics at three medical centers. PATIENTS: Patients had C. neoformans grown in culture from cerebrospinal fluid. Primary therapy consisted of either 2.0 g of amphotericin B alone; 6 weeks of combination therapy with flucytosine; or, if flucytosine was poorly tolerated, an adjusted minimum total amphotericin B dose. To meet criteria for adequate treatment of meningitis all patients had two sequential cerebrospinal fluid samples which were culture negative. MEASUREMENTS AND MAIN RESULTS: Nine of forty-one patients grew C. neoformans from urine after completion of primary treatment, but none had urinary symptoms. Fungi were visualized in expressed prostatic secretions in 4 of these patients. One patient refused further treatment and developed cryptococcemia within 5 weeks. Three patients received additional amphotericin B; all had persistent funguria without systemic relapse. Six patients received fluconazole; 4 became urine culture negative, and 2 had systemic relapse. CONCLUSION: The persistence of urinary C. neoformans after adequate therapy for meningitis suggests that the urinary tract (probably the prostate) is a sequestered reservoir of infection from which systemic relapse may occur.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Cryptococcus neoformans isolated from human dwellings in Rio de Janeiro, Brazil: an analysis of the domestic environment of AIDS patients with and without cryptococcosis.

One hundred and fifty-four human dwellings in the metropolitan area of Rio de Janeiro, Brazil were studied. A total of 824 samples of indoor dust, outdoor soil and avian droppings were collected. Cryptococcus neoformans var. neoformans was isolated from 20 (13%) dwellings, comprising five (15.6%) of 32 dwellings of patients with AIDS-associated cryptococcosis; four (8.9%) of 45 dwellings of patients with AIDS but without cryptococcosis; and 11 (14.3%) of 77 dwellings of apparently healthy individuals (P>0.05). The principal factor associated with domiciliar contamination by C. neoformans var. neoformans was the presence of avians in the domestic environment or nearby the home. Cryptococcosis was more frequent among AIDS patients residing in dwellings from which C. neoformans var. neoformans was isolated than among AIDS patients from whose domestic environment the fungus was not demonstrated by the methods used (odds ratio (OR)=2.05). These findings suggest that the distribution of C. neoformans var. neoformans in Rio de Janeiro is not restricted to the classically known biotopes as well as reinforce the possibility of exogenous infection in opportunistic cryptococcosis, including exogenous infection acquired in the domestic environment.

AIDS-Related Opportunistic Infections↗
PubMed1998

First isolation of Cryptococcus neoformans var. gattii, serotype C, from the environment in Colombia.

The natural habitat of Cryptococcus neoformans var. gattii, serotype B in the environment was established by Australian investigators who demonstrated its association with species of Eucalyptus. The aim of the present study was to search for the habitat of this variety in a city of Colombia, where clinical cases due to this variety occur with great frequency. For a period of 5 months detritus, vegetable material and air samples in and around 68 almond trees (Terminalia catappa) located in the city were studied. C. neoformans var. gattii serotype C was the only variety isolated from two of the 68 trees sampled. These trees were positive for 4 of the 5 months during which they were studied. From the first positive sample kept under refrigeration, it was possible to isolate the fungus up to 3 months later. This is the first report of the isolation of serotype C from the environment. More studies are required in order to establish the ecological significance of this finding.

Air Microbiology↗
PubMed1999

Inositol acylation of glycosylphosphatidylinositols in the pathogenic fungus Cryptococcus neoformans and the model yeast Saccharomyces cerevisiae.

Cryptococcus neoformans, an opportunistic fungus responsible for life-threatening infection in immunocompromised patients, is able to synthesize glycosylphosphatidylinositol (GPI) structures. Radiolabelling experiments in vitro with the use of a cryptococcal cell-free system showed that the pathway begins as in other eukaryotes, with the addition of N-acetylglucosamine to phosphatidylinositol, followed by deacetylation of the sugar residue. The third step, acylation of the inositol ring, seemed to involve a fatty acid other than palmitate, in contrast with previous findings in Saccharomyces cerevisiae and mammalian GPI pathways. A systematic study of inositol acylation in C. neoformans and S. cerevisiae showed that both organisms used a variety of fatty acids in this step; these were transferred directly from acyl-CoA to inositol without modification. However, the specificity of fatty acid utilization was quite distinct in the two fungi, with the pathogen being substantially more restrictive. In mammalian cells fatty acids added exogenously as acyl-CoAs are not transferred directly to inositol. These results suggest significant differences in the GPI biosynthetic pathway between mammalian and C. neoformans cells that could represent targets for anti-cryptococcal therapy.

Acetylglucosamine↗
PubMed1998

[The identification of Cryptococcus neoformans var. neoformans in Cuban clinical isolates].

50 strains of Cryptococcus neoformans of clinical origin were studied by using the canavanine-glycine-bromothymol blue (CGB) medium. 56% of the strains were isolated from AIDS patients, and 16% belonged to patients with kidney transplantation. 90% of the samples were obtained from the samples of cerebrospinal fluid, which corresponded to the classical form of presentation of cryptococcosis. All the strains were identified as C. neoformans var. neoformans, coinciding with previous reports made in Cuba. Knowing the varieties of C. neoformans, inferences can be drawn on the epidemiology, clinics and response to the treatment of cryptococcosis.

Acquired Immunodeficiency Syndrome↗
PubMed1998

[The evaluation of the specific type of capsular polysaccharide of Cryptococcus neoformans as an immunogen and positive-control antigen].

The specific type of capsular polysaccharide of an autochthonous strain of Cryptococcus neoformans var. neoformans was obtained by using the method of selective precipitation with hexadimethrine bromide. The capsular polysaccharide was matched to lamb's erythrocytes and it was used as an immunogen in rabbits. Antibody titres of up to 1:32 were attained. Doble serial dilutions of the capsular polysaccharide were evaluated as positive control antigen by contraimmunoelectrophoresis, latex and ELISA techniques, showing biological activity.

Animals↗
PubMed1999

[Meningitis by Cryptococcus neoformans in patients with HIV infection].

OBJECTIVE: To review a serie of patients with cryptococcal meningitis and immunodeficiency syndrome (AIDS) treated in our hospital in the last two years. PATIENTS AND METHODS: Retrospective study of 25 patients infected with the human immunodeficiency virus (HIV) and affected by Cryptococcus neoformans meningitis. The factors analysed were epidemiological data, clinical manifestations, biochemical and microbiological characteristics of cerebrospinal fluid (CSF), radiological abnormalities, treatment, adverse reactions and outcomes. RESULTS: Eighty-four percent of patients had less than 200 CD4/microliter. Cryptococcal infection was the AIDS defining illness in 24% of cases. Patients typically presented with neurologic symptoms such as: headache (88%), fever (68%) and somnolence (68%); 20% presented seizures and 28% focal deficits. There were no CSF biochemical alterations in 25% of them. CSF culture and indian ink stain were positive in 76%. CSF cryptococcal antigen test was positive in 68% of the cases. TC showed abnormalities in 48%. CSF of all patients treated with amphotericin B (AB) plus flucytosine (5FC) whose CSF culture was monitored became negative in the first two weeks, meanwhile those treated only with AB or fluconazol had negative control culture in 60% and 50% respectively. Six patients died within the initial 10 weeks. Death was due to bacterian sepsis in 3 patients and high intracranial pressure was the cause in 2 cases. One happened before treatment was administered. CONCLUSIONS: It's essential to consider the possibility of cryptococcal meningitis in patients infected with HIV and any compatible symptom regardless of CSF biochemical results and immunodepression level (CD4). Although our study was non randomized and so we can't propose a therapeutical schedule based on it, we can say that patients treated with AB plus 5FC showed an earlier conversion from positive to negative CSF cultures without more adverse reactions.

Adult↗
PubMed1999

Production of nitric oxide by rat alveolar macrophages stimulated by Cryptococcus neoformans or Aspergillus fumigatus.

Cryptococcus neoformans and Aspergillus fumigatus are airborne fungi and the alveolar macrophages (AM) constitute a first line of host defence against both pathogens. We investigated the ability of rat AM to produce nitric oxide (NO) when challenged in vitro with C. neoformans, A. fumigatus conidia or inert silica particles alone and together with interferon gamma (IFN-Gamma). The role of NO in the killing of C. neoformans as well as the relationship between phagocytosis of the yeast or A. fumigatus conidia and NO production by AM were studied. Both fungi, but not the inert particles induced a small but significant increase in NO production by AM. A synergistically enhanced NO production by AM was observed when each fungus, but not silica particles, were incubated together with IFN-Gamma. AM treated with IFN-Gamma and challenged with C. neoformans showed higher killing activity than untreated AM, a finding that correlated with increased NO production by AM. Both effects were reduced by an inhibitor of NO synthesis. Increased NO production by IFN-Gamma activated AM was found together with an increased accumulated attachment of A. fumigatus conidia and serum opsonized, but not unopsonized C. neoformans. The IFN-Gamma dependent increase in accumulated attachment of the fungi might be responsible for the synergistic effect of the fungi and IFN-Gamma on the NO production. Our data suggest that activated rat AM might efficiently use the antimicrobial nitric oxide system in the defence against these pathogens in the normal host.

Animals↗
PubMed1999

Scanning electron microscopy of encapsulated and non-encapsulated Cryptococcus neoformans and the effect of glucose on capsular polysaccharide release.

Cryptococcus neoformans has a polysaccharide capsule composed primarily of glucuronoxylomannan (GXM). This study focuses on the morphology of both encapsulated and non-encapsulated organisms in the presence and absence of monoclonal antibodies (mAbs) and serum proteins, and the effect of glucose on capsular polysaccharide release. Examination of the encapsulated C. neoformans strains 24067 and 34873 by scanning electron microscopy (SEM) revealed globular cells covered with a loose fibrillar network which was most prominent during the early stationary phase. In the presence of GXM-binding mAbs or serum the capsule border became distinct and bud scars were evident in the fibrillar network. In contrast, SEM of strain 52817, a non-encapsulated mutant of 34873 revealed ovoid cells devoid of a fibrillar network with bud scars and small surface protrusions. mAb 2H1 bound to cells from strains 24067 and 34873 but not 52817. No GXM was detected in supernatants of 52817 culture. For several strains, there was significantly more GXM in culture supernatants using high glucose media. In summary, our results indicate: i) SEM methods for studying capsular structure in C. neoformans; ii) no reactivity by GXM-binding mAb with a non-encapsulated strain; iii) the presence of distinctive bud scars in both encapsulated and non-encapsulated cells; and iv) dependence of GXM concentration on glucose concentration in culture media. The implications of these results are discussed.

Animals↗
PubMed1999

Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans.

After intratracheal inoculation of the AIDS-associated pathogen Cryptococcus neoformans, 12-wk survival was >90% for CCR5+/+ mice but <25% for CCR5-/- mice. There were no defects in lung leukocyte recruitment (wk 5), pulmonary clearance, or delayed-type hypersensitivity in CCR5-/- mice. However, CCR5-/- mice had defects in leukocyte recruitment into the brain and, strikingly, in elimination of cryptococcal polysaccharide from the brain. In nonimmune CCR5-/- mice, there was a significant defect in macrophage recruitment after challenge with shed cryptococcal products (C. neoformans filtrate Ag) but not other nonspecific stimuli. Thus, CCR5 plays specific roles in innate immunity and organ-specific leukocyte trafficking during host defense against C. neoformans.

Animals↗