Sur7 promotes plasma membrane organization and is needed for resistance to stressful conditions and to the invasive growth and virulence of Candida albicans.

The human fungal pathogen Candida albicans causes lethal systemic infections because of its ability to grow and disseminate in a host. The C. albicans plasma membrane is essential for virulence by acting as a protective barrier and through its key roles in interfacing with the environment, secretion of virulence factors, morphogenesis, and cell wall synthesis. Difficulties in studying hydrophobic membranes have limited the understanding of how plasma membrane organization contributes to its function and to the actions of antifungal drugs. Therefore, the role of the recently discovered plasma membrane subdomains termed the membrane compartment containing Can1 (MCC) was analyzed by assessing the virulence of a sur7Δ mutant. Sur7 is an integral membrane protein component of the MCC that is needed for proper localization of actin, morphogenesis, cell wall synthesis, and responding to cell wall stress. MCC domains are stable 300-nm-sized punctate patches that associate with a complex of cytoplasmic proteins known as an eisosome. Analysis of virulence-related properties of a sur7Δ mutant revealed defects in intraphagosomal growth in macrophages that correlate with increased sensitivity to oxidation and copper. The sur7Δ mutant was also strongly defective in pathogenesis in a mouse model of systemic candidiasis. The mutant cells showed a decreased ability to initiate an infection and greatly diminished invasive growth into kidney tissues. These studies on Sur7 demonstrate that the plasma membrane MCC domains are critical for virulence and represent an important new target for the development of novel therapeutic strategies. IMPORTANCECandida albicans, the most common human fungal pathogen, causes lethal systemic infections by growing and disseminating in a host. The plasma membrane plays key roles in enabling C. albicans to grow in vivo, and it is also the target of the most commonly used antifungal drugs. However, plasma membrane organization is poorly understood because of the experimental difficulties in studying hydrophobic components. Interestingly, recent studies have identified a novel type of plasma membrane subdomain in fungi known as the membrane compartment containing Can1 (MCC). Cells lacking the MCC-localized protein Sur7 display broad defects in cellular organization and response to stress in vitro. Consistent with this, C. albicans cells lacking the SUR7 gene were more susceptible to attack by macrophages than cells with the gene and showed greatly reduced virulence in a mouse model of systemic infection. Thus, Sur7 and other MCC components represent novel targets for antifungal therapy.

An internal polarity landmark is important for externally induced hyphal behaviors in Candida albicans.

Directional growth is a function of polarized cells such as neurites, pollen tubes, and fungal hyphae. Correct orientation of the extending cell tip depends on signaling pathways and effectors that mediate asymmetric responses to specific environmental cues. In the hyphal form of the eukaryotic fungal pathogen Candida albicans, these responses include thigmotropism and galvanotropism (hyphal turning in response to changes in substrate topography and imposed electrical fields, respectively) and penetration into semisolid substrates. During vegetative growth in C. albicans, as in the model yeast Saccharomyces cerevisiae, the Ras-like GTPase Rsr1 mediates internal cellular cues to position new buds in a prespecified pattern on the mother cell cortex. Here, we demonstrate that Rsr1 is also important for hyphal tip orientation in response to the external environmental cues that induce thigmotropic and galvanotropic growth. In addition, Rsr1 is involved in hyphal interactions with epithelial cells in vitro and its deletion diminishes the hyphal invasion of kidney tissue during systemic infection. Thus, Rsr1, an internal polarity landmark in yeast, is also involved in polarized growth responses to asymmetric environmental signals, a paradigm that is different from that described for the homologous protein in S. cerevisiae. Rsr1 may thereby contribute to the pathogenesis of C. albicans infections by influencing hyphal tip responses triggered by interaction with host tissues.

Virulence and karyotype analyses of rad52 mutants of Candida albicans: regeneration of a truncated chromosome of a reintegrant strain (rad52/RAD52) in the host.

The virulence of Candida albicans mutants lacking one or both copies of RAD52, a gene involved in homologous recombination (HR), was evaluated in a murine model of hematogenously disseminated candidiasis. In this study, the virulence of the rad52Delta mutant was dependent upon the inoculum concentration. Mice survived at a cell inoculum of 1 x 10(6), but there was a decrease in survival time at dosages of 1.5 x 10(6) and especially at 3 x 10(6) cells per animal. The heterozygote RAD52/rad52 behaved like wild type, whereas a reintegrant strain was intermediate in its ability to cause death compared to these strains and to the avirulent rad52/rad52 null at inocula of 1 x 10(6) and 1.5 x 10(6) cells. A double mutant, lig4/lig4/rad52/rad52, was avirulent at all inocula used. PCR analysis of the RAD52 and/or LIG4 loci showed that all strains recovered from animals matched the genotype of the inoculated strains. Analysis of the electrophoretical karyotypes indicated that the inoculated, reintegrant strain carried a large deletion in one copy of chromosome 6 (the shortest homologue, or Chr6b). Interestingly, truncated Chr6b was regenerated in all the strains recovered from moribund animals using the homologue as a template. Further, regeneration of Chr6b was paralleled by an increase in virulence that was still lower than that of wild type, likely because of the persistent loss of heterozygosity in the regenerated region. Overall, our results indicate that systemic candidiasis can develop in the absence of HR, but simultaneous elimination of both recombination pathways, HR and nonhomologous end-joining, suppresses virulence even at very high inocula.

[Parasitoses in immune deficiences]. / Parazytozy w stanach niedoborów immunologicznych.

The congenital or acquired cause the state of immune deficiency. To acquired factors belong immunosuppressive therapy after grafting and in systemic diseases as infections with HIV. There is a number of parasitic organisms, mainly protozoa, which preferentially settle in immunocompromised persons. The opportunistic parasites are present in the nearest environment. Some of them were newly recognized as human invaders. The state of immune deficiency may reactivate latent infections, that occurs with Toxoplasma gondii infection. Some parasitic infections which are benign and self- resolving, when affecting immunocompetent hosts, become fulminant or disseminated and very often life - threatening in immunosuppressed individuals.

Failure of systemic empirical treatment with amphotericin B to prevent candidemia in neutropenic patients with cancer.

We undertook a retrospective review of all patients with hematologic malignancies in whom candidemia developed during chemotherapy-induced neutropenia in 1989 and 1990. Candidemia developed in 11 patients; five were receiving therapeutic doses of amphotericin B at the time of infection. Disseminated infection occurred in 2 of 5 patients with breakthrough infection and 3 of 6 patients with candidemia before receipt of amphotericin B. Among patients with breakthrough candidemia there was a trend toward more-prolonged neutropenia prior to infection (P = .069), but otherwise they were indistinguishable from other candidemic patients with regard to risk factors for candidemia. Amphotericin B-susceptible Candida albicans was isolated from two patients and Candida krusei from three patients with breakthrough infection. All patients were treated with amphotericin B; all breakthrough infections responded to treatment. Neutropenic patients with breakthrough candidemia were clinically similar to those whose candidemia preceded amphotericin B therapy, and there was no increase in morbidity and mortality among individuals with breakthrough infection.

[Growth rate of Candida albicans (Robin, 1853)and Candida stellatoidea (Martin et Jones, 1938) isolated from the human respiratory system]. / Tempo wzrostu Candida albicans (Robin, 1853) i Candida stellatoidea (Martin et Jones, 1938) izolowanych z ukladu oddechowego czlowieka.

The study comprises an analysis of the growth rate of C. albicans and C. stellatoidea strains isolated from the respiratory system and incubated on Nickerson's and Sabouraud's agar in the dark and by light. The property to form hyphae and pseudohyphae by both species was used to evaluate the growth rate. The increase in their growth allowed to isolate the stages characteristic for growth and development of most fungi. Disturbances appeared with the fungi exposed to light which is the factor definitely setting back the growth. Faster growth and development was observed with C. stellatoidea.

Systemic candidiasis from Candida albicans colonizing the gastrointestinal tract of mice.

Reproducible induction of systemic Candida infection was achieved by treating mice in which Candida colonization had been established in the gastrointestional tract by aminobenzylpenicillin treatment. Systemic candidiasis was induced in these mice by X-ray irradiation followed by immunosuppressive doses of dexamethasone or X-ray irradiation followed by immunosuppressive doses of trypan blue. Macrophages seem to play an important role in thie systemic infection.

[Gastric candidiasis. Report of a case]. / Candidiásis gástrica. Reporte de un caso.

One patient was seen with Candida albicans infection in a gastric ulcer. Gastric biopsy was of value in the diagnosis. The patient responded well to Nistatin therapy.