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PubMed1994

Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neoformans.

Passive antibody administration is a potentially useful approach for the therapy of human Cryptococcus neoformans infections. To evaluate the efficacy of the human immunoglobulin G1 (IgG1) constant region against C. neoformans and to construct murine antibody derivatives with reduced immunogenicities and longer half-lives in humans, two mouse-human IgG1 chimeric antibodies were generated from the protective murine monoclonal antibodies 2D10 (IgM) and 18B7 (IgG1). The 2D10 mouse-human IgG1 chimeric antibody (ch2D10) had significantly lower binding affinity than its parent murine antibody (m2D10), presumably because of a loss of avidity contribution on switching from IgM to IgG. The 18B7 mouse-human IgG1 chimeric antibody (ch18B7) had higher affinity for cryptococcal polysaccharide antigen than its parent murine antibody (m18B7). ch18B7 and ch2D10 promoted phagocytosis of C. neoformans by primary human microglial cells and the murine J774.16 macrophage-like cell line. ch18B7 and m18B7 enhanced fungistatic or fungicidal activity of J774.16 cells and prolonged the survival of lethally infected mice. We conclude that the human IgG1 constant chain can be effective in mediating antifungal activity against C. neoformans. ch18B7 or similar antibodies are potential candidates for passive antibody therapy of human cryptococcosis.

Animals↗
PubMed1991

Cryptococcus neoformans serotype A glucuronoxylomannan-protein conjugate vaccines: synthesis, characterization, and immunogenicity.

We synthesized Cryptococcus neoformans serotype A glucuronoxylomannan (GXM) conjugate vaccines under conditions suitable for human use to prevent disseminated cryptococcosis. The purified, sonicated GXM was derivatized with adipic acid dihydrazide through either hydroxyl or carboxyl groups and then covalently bound to tetanus toxoid (TT) or Pseudomonas aeruginosa exoprotein A (rEPA). The immunogenicity of these conjugates was evaluated in BALB/c and general purpose mice by subcutaneous injection in saline. The conjugates elicited higher GXM antibody responses than GXM alone. Booster immunoglobulin G (IgG) and IgM responses were elicited by all conjugates in BALB/c mice. The conjugates prepared through hydroxyl activation (GXM-TT2 and GXM-rEPA) were more immunogenic than the one prepared through carboxyl activation (GXM-TT1). GXM antibody response was enhanced by the administration of monophosphoryl lipid A 2 days following the injection of GXM-TT2 (P less than 0.03). The conjugates also elicited IgG antibodies to the carrier proteins. Gel diffusion tests using conjugate-induced hyperimmune sera and chemically modified GXMs suggested that the specificity of GXM-TT1-induced antibodies was conferred by the O-acetyl groups. Hyperimmune sera generated by GXM-TT2 precipitated with the chemically unmodified and the de-O-acetylated GXMs but not with the carboxyl-reduced and de-O-acetylated GXM. GXM-TT2-induced hyperimmune serum also precipitated with the capsular polysaccharides of C. neoformans serotypes D, B, and C. The conjugate vaccines prepared through hydroxyl activation of the GXM are sufficiently immunogenic and appear to be suitable for clinical evaluation.

Animals↗
PubMed1999

Antibody response to Cryptococcus neoformans proteins in rodents and humans.

The prevalence and specificity of serum antibodies to Cryptococcus neoformans proteins was studied in mice and rats with experimental infection, in individuals with or without a history of potential laboratory exposure to C. neoformans, human immunodeficiency virus (HIV)-positive individuals who developed cryptococcosis, in matched samples from HIV-positive individuals who did not develop cryptococcosis, and in HIV-negative individuals. Rodents had little or no serum antibody reactive with C. neoformans proteins prior to infection. The intensity and specificity of the rodent antibody response were dependent on the species, the mouse strain, and the viability of the inoculum. All humans had serum antibodies reactive with C. neoformans proteins regardless of the potential exposure, the HIV infection status, or the subsequent development of cryptococcosis. Our results indicate (i) a high prevalence of antibodies reactive with C. neoformans proteins in the sera of rodents after cryptococcal infection and in humans with or without HIV infection; (ii) qualitative and quantitative differences in the antibody profiles of HIV-positive individuals; and (iii) similarities and differences between humans, mice, and rats with respect to the specificity of the antibodies reactive with C. neoformans proteins. The results are consistent with the view that C. neoformans infections are common in human populations, and the results have implications for the development of vaccination strategies against cryptococcosis.

AIDS-Related Opportunistic Infections↗
PubMed1994

Cutaneous involvement with Cryptococcus neoformans in AIDS.

Patients infected with HIV are susceptible to many opportunistic fungal infections. Cryptococcus neoformans infection is particularly common in patients with AIDS. We describe a patient with disseminated cryptococcosis resembling molluscum contagiosum and review the typical cutaneous manifestations of disseminated cryptococcosis. A synopsis of case reports in the English literature is also presented.

AIDS-Related Opportunistic Infections↗
PubMed2001

Serotype AD strains of Cryptococcus neoformans are diploid or aneuploid and are heterozygous at the mating-type locus.

Cryptococcus neoformans is a pathogenic basidiomycete with a defined sexual cycle involving mating between haploid yeast cells with a transient diploid state. C. neoformans occurs in four predominant serotypes (A, B, C, and D), which represent different varieties or species. Rare clinical and environmental isolates with an unusual AD serotype have been reported and suggested to be diploid. We found by fluorescence-activated cell sorter analysis that serotype AD strains are aneuploid or diploid. PCR analysis with primers specific for serotype A or D alleles of the CNA1, CLA4, and GPA1 genes revealed that both alleles are often present in serotype AD strains. PCR analysis with primers specific for genes in the MATa or MATalpha mating-type loci revealed that serotype AD strains are heterozygous for the mating-type locus. Interestingly, in several serotype AD strains, the MATalpha locus was derived from the serotype D parent and the MATa locus was inherited from a serotype A parent that has been thought to be extinct. Basidiospores from a self-fertile serotype AD strain bearing the putative serotype A MATa locus showed a very low viability ( approximately 5%), and no fertile serotype A MATa strain could be recovered. Serotype AD strains were virulent in a murine model. Hybrid AD strains could readily be isolated following a laboratory cross between a serotype A strain and a serotype D strain. In summary, serotype AD strains of C. neoformans are unusual aneuploid or diploid strains that result from matings between serotype A and D strains. Self-fertile isolates fail to undergo normal meiosis because of genetic divergence. Our findings further suggest that serotype A MATa strains may exist in nature.

Aneuploidy↗
PubMed1994

Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence.

Capsule formation plays a significant role in the pathogenicity of Cryptococcus neoformans. To study the molecular basis of capsule synthesis, the capsule-deficient phenotype of a mutant strain was complemented by transformation. A plasmid rescued from the resulting Cap+ transformant complemented a cap59 mutation which was mapped previously by classical recombination analysis. Gene deletion by homologous integration resulted in an acapsular phenotype, indicating that we have identified the CAP59 gene. The CAP59 gene was assigned to chromosome I by Southern blot analysis of contour-clamped homogeneous electric field gel electrophoresis-resolved chromosomes of C. neoformans var. neoformans. Sequence comparison of genomic and cDNA clones indicated the presence of six introns. CAP59 encoded a 1.9-kb transcript and a deduced protein of 458 amino acids. Analysis of the nucleotide sequence revealed little similarity to existing sequences in the data bank. When the capsule-deficient phenotype was complemented, the originally avirulent C. neoformans strain became virulent for mice. In addition, the acapsular strain created by gene deletion of CAP59 lost its virulence. This work demonstrates the molecular basis for capsule-related virulence and that the CAP59 gene is required for capsule formation.

Amino Acid Sequence↗
PubMedDate not supplied

Vertical transmission of Cryptococcus neoformans from a mother coinfected with human immunodeficiency virus: case report.

Disseminated infection with Cryptococcus neoformans was observed in a newborn infant who presented fever and respiratory symptoms since the 52 nd day of life. The mother was infected by human immunodeficiency virus and presented pulmonary and meningeal cryptococcal infection. This is a rare case of cryptococcal infection with probable maternal-fetal transmission.

AIDS-Related Opportunistic Infections↗
PubMed1982

Antigenic characterization of Cryptococcus neoformans serotypes and its application to serotyping of clinical isolates.

Antigenic analysis of the four serotypes of Cryptococcus neoformans was carried out by slide agglutination with reciprocal adsorption methods. With this procedure the antigenic patterns of the serotypes were established. Serotypes A and D had antigenic factors 1, 2, 3, 7 and 1, 2, 3, 8, respectively. Serotypes B and C were found to have antigenic factors 1, 2, 4, 5 and 1, 4, 6, respectively. Factor sera, prepared according to the antigenic patterns demonstrated by adsorption studies, proved to be useful for rapidly and accurately identifying C. neoformans serotypes. Some patterns similar to those of the C. neoformans serotypes were observed in five other Cryptococcus species and two Candida species. The proton magnetic resonance spectra of polysaccharides from the C. neoformans serotypes correlated well with their antigenic characteristics. Phenol oxidase test reactions and growth at 37 degrees C were useful criteria for determining which yeasts should be chosen for clinical application of factor sera for serotyping of C. neoformans. Sixty-two Japanese isolates of C. neoformans were serotyped. Fifty-eight of these isolates were serotype A, three were serotype A-D, and one was serotype D.

Agglutination Tests↗
PubMed1986

Isolation of highly encapsulated Cryptococcus neoformans serotype B from a patient in New York City.

For the first time, Cryptococcus neoformans serotype B was isolated from a patient in New York City, not a region endemic for B/C serotypes. The isolate was morphologically unusual, with cells several times larger in infected tissue than those characteristic of the yeastlike pathogen. This anomaly may be a problem in the identification of similar isolates. Two serotype differentiation media and a slide agglutination test were used for definitive serotype identification.

Cryptococcosis↗
PubMed2004

A new caffeic acid minimal synthetic medium for the rapid identification of Cryptococcus neoformans isolates.

Melanin production is one of the most important criteria for rapid identification of Cryptococcus neoformans. Most of the media described in the literature for identifying C. neoformans are very complex; they contain many organic or inorganic compounds and are difficult to prepare and store. The new minimal synthetic caffeic acid medium described in this paper is simpler to prepare, convenient and constitutes an interesting new medium for the rapid identification of C. neoformans isolates.

Caffeic Acids↗
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↗
PubMed2003

Phenotypic switching of Cryptococcus neoformans can influence the outcome of the human immune response.

The human pathogenic fungus Cryptococcus neoformans exhibits the phenomenon of phenotypic switching, a process that generates variant colonies that can differ in morphology, virulence and other characteristics such as capsular glucuronoxylomannan (GXM) size and structure. A previous study established that mucoid colony (MC) variants of C. neoformans were more virulent and elicited a different inflammatory response than smooth colony (SM) variants. In this study, we investigated the interaction of cells from MC and SM variants and their respective GXMs with human T cells and monocytes. Specifically, we measured CD40, CD80 and CD86 expression, lymphoproliferation and interleukin (IL)-4, IL-10, interferon (IFN)-gamma and IL-12Rbeta2 expression in the presence and absence of variant cells and their GXMs. For some immune parameters, both MC and SM strains produced similar results, in particular no differences were observed in IL-4 induction. However, for other critical parameters, including CD86 expression, lymphoproliferation and IL-10 production, the MC variant had effects that can be expected to impair the immune response. Hence, a single C. neoformans strain can elicit several different immune responses depending on the colony type expressed, and this is unlikely to be accounted for by differences in phagocytosis only. The results provide a potential explanation for the higher virulence of the MC variant based on the concept that these cells inhibit the development of a vigorous immune response. Furthermore, the results suggest a mechanism by which phenotypic switching can generate variants able to evade the immune response.

Antigen-Presenting Cells↗
PubMed1995

Virulence of Cryptococcus neoformans serotypes A, B, C and D for four mouse strains.

The relative virulence of Cryptococcus neoformans serotypes A, B, C and D in four mouse strains was assessed by measuring their migration from the foot-pad of the animals to the spleen, lungs and brain in 6-week-old DBA/2, BALB/c, A/J and a hybrid mouse strain by re-isolating yeasts from the internal organs. Comparable doses of each C. neoformans serotype were inoculated into the foot-pads of the mice. C. neoformans var neoformans strains A68, D52, A-(IN) and D-(IN) were more virulent than C. neoformans var gatti strains B112 and C18. However, the differences in the relative virulence of the var neoformans and the var gatti serotypes for the mouse strains were not significant (p > 0.05). Re-isolation of yeasts from mice showed that the BALB/c mice, in particular, and the DBA/2 mice were more susceptible to disseminated C. neoformans infection. The virulence of C. neoformans serotypes through foot-pad inoculation of mice was established.

Animals↗
PubMed2006

Trypanosoma lewisi-induced immunosuppression: the effects on alveolar macrophage activities against Cryptococcus neoformans.

The immunosuppressive effect of Trypanosoma lewisi infection on alveolar macrophage (AM) activities against Cryptococcus neoformans was studied in an animal model. Two groups of rats were treated with T. lewisi and killed after 4 (4d-rats) and 7 days (7d-rats), respectively. A third group not given T. lewisi, served as control. AM were challenged in vitro with C. neoformans. Phagocytosis was assessed with a fluorescence method. Superoxide anion production was evaluated with the nitroblue tetrazolium (NBT) test. The survival of cryptococci was estimated by counting colony-forming units. The numbers of detached AM from culture plates were determined using a Bürker chamber. The NBT response, adhesion to plate surface and killing activity, but not the phagocytosis of AM from 4d-rats were significantly impaired compared to control or 7d-rats. Thus, T. lewisi causes transitory immunosuppressive effects on AM activities. This rapid T. lewisi immunosuppression model may be useful to study new approaches to anticryptococcal therapy.

Animals↗
PubMed1991

Rapid method to extract DNA from Cryptococcus neoformans.

A rapid and easy method for the extraction of total cellular DNA from Cryptococcus neoformans is described. This procedure modifies and considerably simplifies previously reported methods. Numerous steps were either eliminated or replaced, including preincubations with cell wall permeability agents such as beta-mercaptoethanol and dithiothreitol. The commercially available enzyme preparation Novozyme 234 was found to contain a potent concentration of DNases which actively degrade DNA. Degradation and loss of DNA was prevented by maintaining a high concentration of EDTA in the lysing solution. This procedure resulted in high yields (150 to 200 micrograms of DNA from 100 ml of culture) of good-quality (undegraded), high-molecular-weight DNA which was readily digested by restriction endonucleases, making it suitable for use in various molecular applications.

Cryptococcus neoformans↗
PubMed1999

Cryptococcus neoformans in bird excreta in the city zoo of Cali, Colombia.

The presence of Cryptococcus neoformans was studied in bird excreta and in the air circulating in and around bird cages in the City Zoo of Cali, Colombia, between August 1994 and April 1995, using a sunflower seed agar culture medium for fungus isolation. A total of 380 samples was studied, 110 from droppings and 270 from Petri dishes placed inside (148) and outside (122) the cages. C. neoformans var neoformans was found in only two cases, one from bird excreta (0.9%) and the other from air inside a cage (0.7%). The former positive sample was collected from the cracks of a dead tree where two crested caracaras (Polyborus plancus) roosted; the feces were dry, accumulated, and with a pH of 6. The other positive sample was found inside the cage of these birds; however, samples taken in a dispersion study at 0.5, 1, 5 and 10 m around this cage were all negative. It appears that this low isolation rate is due to adequate cleaning and disinfection procedures used in the city zoo of Cali.

Air Microbiology↗
PubMed1996

Synthesis of a pentasaccharide corresponding to the repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar D.

The assembly of the pentasaccharide repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar D (i.e. 1) is described. The glucuronic acid residue in 1 is introduced as a glucopyranoside and oxidized in a later stage of the synthesis. Thus, iodonium ion-assisted glycosylation of the partially protected methyl mannopyranoside 11 with ethylthio donor 14 gave, after selective deprotection, disaccharide 18. Elongation of the latter with D-glucopyranoside 35 gave trisaccharide 36. Subsequent protective group manipulations yielded the acceptor 37. Condensation of disaccharide donor 31 with trisaccharide acceptor 37 yielded pentasaccharide 38. Protective group manipulations of 38 afforded 42, the glucoside of which was oxidized to yield the corresponding glucuronide 44. Hydrogenolysis of 44 gave the target pentasaccharide 1.

Carbohydrate Sequence↗
PubMed2002

Effect of auristatin PHE on microtubule integrity and nuclear localization in Cryptococcus neoformans.

The mechanism of action of the fungicidal peptide auristatin PHE was investigated in Cryptococcus neoformans. Since auristatin PHE causes budding arrest in C. neoformans (T. Woyke, G. R. Pettit, G. Winkelmann, and R. K. Pettit, Antimicrob. Agents Chemother. 45:3580-3584, 2001), microtubule integrity and nuclear localization in auristatin PHE-treated cells were examined. Iterative deconvolution in conjunction with an optimized C. neoformans microtubule immunolabeling procedure enabled detailed visualization of the microtubule cytoskeleton in auristatin PHE-treated C. neoformans. The effect of auristatin PHE on C. neoformans microtubule organization was compared with that of the tubulin-binding agent nocodazole. Both drugs produced complete disruption first of cytoplasmic and then of spindle microtubules in a time- and concentration-dependent manner. Sub-MICs of auristatin PHE caused complete microtubule disruption within 4.5 h, while 1.5 times the nocodazole MIC was required for the same effect. For both drugs, disruption of microtubules was accompanied by blockage of nuclear migration and of nuclear and cellular division, resulting in cells arrested in a uninucleate, large-budded stage. Nocodazole and the linear peptide auristatin PHE are remarkably different in structure and spectrum of activity, yet on the cellular level, they have similar effects.

Cryptococcus neoformans↗