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Françoise Dromer

Publications and source records attributed to Françoise Dromer.

28 records · Page 2Linked to original sources
PubMed2003

Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans.

Itraconazole is a fungistatic agent that, although highly lipophilic, shows poor transport through the blood brain barrier that may be due to efflux proteins. The combined administration of an efflux inhibitor with itraconazole should increase cerebral itraconazole concentrations and therefore, improve the treatment of Cryptococcus neoformans meningitis with this antifungal agent. To test this hypothesis, we have studied the influence of murine cerebral infection with C. neoformans and the inhibition of efflux by intraperitoneal injection of a P-glycoprotein inhibitor, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], on the pharmacokinetics of itraconazole in plasma and brain after a single intraperitoneal itraconazole injection. We also investigated the influence of efflux inhibition on the efficacy of repeated doses of itraconazole in this murine model. The results showed that in healthy and infected mice pretreated or not with GF120918, plasma itraconazole values of area under the curve (AUC) were similar. In contrast, cerebral values of AUC were higher in infected mice compared with healthy mice. Moreover, the pretreatment of infected mice with GF120918 significantly increased cerebral itraconazole values of area under the curve and decreased weight loss in the treatment with itraconazole of a cerebral infection with C. neoformans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

In vitro interaction of flucytosine with conventional and new antifungals against Cryptococcus neoformans clinical isolates.

Combinations of flucytosine with conventional and new antifungals were evaluated in vitro against 30 clinical isolates of Cryptococcus neoformans. Synergy determined by checkerboard analysis was observed with combinations of fluconazole, itraconazole, voriconazole, amphotericin B, and caspofungin with flucytosine against 77, 60, 80, 77, and 67% of the isolates, respectively. Antagonism was never observed. Killing curves showed indifferent interactions between triazoles and flucytosine and synergy between amphotericin B and flucytosine.

Antifungal Agents↗
PubMed2003

Antigenic and biological characteristics of mutant strains of Cryptococcus neoformans lacking capsular O acetylation or xylosyl side chains.

Cryptococcus neoformans is surrounded by an antiphagocytic polysaccharide capsule whose primary constituent is glucuronoxylomannan (GXM). Three prominent structural features of GXM are single xylosyl and glucuronosyl side chains and O acetylation of the mannose backbone. Isogenic pairs of O-acetyl-positive and O-acetyl-negative strains (cas1 Delta) as well as xylose-positive and xylose-negative strains (uxs1 Delta) of serotype D have been reported. The cas1 Delta strains were hypervirulent, and the uxs1 Delta strains were avirulent. The goal of this study was to examine the effects of the cas1 Delta and uxs1 Delta mutations on the following: (i) binding of anti-GXM monoclonal antibodies (MAbs) in capsular quellung reactions, (ii) activation of the complement system and binding of C3, (iii) phagocytosis by neutrophils, and (iv) clearance of GXM in vivo. The results showed that loss of O acetylation produced dramatic changes in the reactivities of five of seven anti-GXM MAbs. In contrast, loss of xylosylation produced a substantive alteration in the binding behavior of only one MAb. O-acetyl-negative strains showed no alteration in activation and binding of C3 from normal serum. Xylose-negative strains exhibited accelerated kinetics for C3 deposition. Loss of O acetylation or xylosylation had no effect on phagocytosis of serum-opsonized yeast cells by human neutrophils. Finally, loss of O acetylation or xylosylation altered the kinetics for clearance of GXM from serum and accumulation of GXM in the liver and spleen. These results show that O acetylation and/or xylosylation are important for binding of anti-GXM MAbs, for complement activation, and for tissue accumulation of GXM but do not impact phagocytosis by neutrophils.

Acetylation↗
PubMed2002

Pathogenesis of cerebral Cryptococcus neoformans infection after fungemia.

The pathogenesis of cerebral infection after Cryptococcus neoformans fungemia in outbred mice was investigated. Confocal microscopy and cultures on ficoll-hypaque gradient-separated blood cells were used to detect yeasts in the cytoplasms of monocytes. In semithin brain sections, poorly capsulated yeasts were seen in macrophages in the leptomeningeal space, in monocytes circulating in leptomeningeal capillaries, or in the endothelial cells themselves, strengthening the hypothesis that monocytes and endothelial cells play key roles in the pathogenesis of cryptococcal meningitis. Similar fungal loads and cellular reactions were seen in mice and in 1 patient with acquired immune deficiency syndrome (AIDS), all with acute cryptococcal meningoencephalitis, and in mice and in 1 patient with AIDS, all with cured cryptococcal infection. Immunostaining revealed both the presence of cryptococcal polysaccharide in various brain cells and antigenic variability both from yeast cell to yeast cell and over time. Thus, our data established the relevance and interest that this experimental model has for investigation of the pathogenesis of human cryptococcal meningitis.

AIDS-Related Opportunistic Infections↗
PubMed2002

Complete glycosylphosphatidylinositol anchors are required in Candida albicans for full morphogenesis, virulence and resistance to macrophages.

Glycosylphosphatidylinositol (GPI)-anchored proteins are involved in cell wall integrity and cell-cell interactions. We disrupted the Candida albicans homologue of the Saccharomyces cerevisiae GPI7/LAS21 gene, which encodes a GPI anchor-modifying activity. In the mutant and on solid media, the yeast-to-hyphae transition was blocked, whereas chlamydospore formation was enhanced. However, the morphogenetic switch was normal in liquid medium. Abnormal budding patterns, cytokinesis and cell shape were observed in both liquid and solid media. The cell wall structure was also modified in the mutants, as shown by hypersensitivity to Calcofluor white. In vitro and in vivo assays revealed that the mutant interacted with its host in a modified way, resulting in reduced virulence in mice and reduced survival in the gastrointestinal environment of mice. The mitogen-activated protein (MAP) kinase pathway of macrophages was downregulated by the wild-type cells but not by the DeltaCagpi7 null strains. In agreement with this abnormal behaviour, mutant cells were more sensitive to the lytic action of macrophages. Our results indicate that a functional GPI anchor is required for full hyphal formation in C. albicans, and that perturbation of the GPI biosynthesis results in hypersensitivity to host defences.

Animals↗
PubMed2002

Isolation and characterization of capsule structure mutant strains of Cryptococcus neoformans.

The capsule of Cryptococcus neoformans is the most obvious virulence factor of this pathogenic yeast. The main capsule constituents are glucuronoxylomannans (GXM). Although several studies have focused on GXM composition and structure, very little is known about their genetics. To elucidate the relationship between the capsule structure and the pathophysiology of the cryptococcosis, genetic screening for mutant strains producing a structurally modified capsule was set up. Using monoclonal antibodies specific for different capsule sugar epitopes, we isolated strains with different mutated capsule structures (Cas mutants). According to their reactivities with various monoclonal antibodies, the mutants were classified into six groups (Cas1 to Cas6). One Cas2 mutant was used to clone the corresponding gene by complementation. This gene (USX1) encodes the previously identified UDP-xylose synthase. We demonstrated that it is necessary for both capsule xylosylation and C. neoformans virulence.

Animals↗
PubMed2002

Synthetic analogues of beta-1,2 oligomannosides prevent intestinal colonization by the pathogenic yeast Candida albicans.

The pathogenic yeast Candida albicans displays at its cell surface beta-1,2 oligomannosides (beta-1,2-Mans). In contrast to the ubiquitous alpha-Mans, beta-1,2-Mans bind to galectin-3, a major endogenous lectin expressed on epithelial cells. The specific role of beta-1,2-Mans in colonization of the gut by C. albicans was assessed in a mouse model. A selected virulent strain of C. albicans (expressing more beta-1,2-Man epitopes) induced more intense and sustained colonization than an avirulent strain (expressing less beta-1,2-Man epitopes). Synthetic (Sigma) beta-and alpha-linked tetramannosides with antigenicities that mimicked the antigenicities of C. albicans-derived oligomannosides were then constructed. Oral administration of Sigmabeta-1,2-Man (30 mg/kg of body weight) prior to inoculation with the virulent strain resulted in almost complete eradication of yeasts from stool samples, whereas administration of Sigmaalpha-Man at the same dose did not. As most cases of human systemic candidiasis are endogenous in origin, this first demonstration that a synthetic analogue of a yeast adhesin can prevent yeast colonization in the gut opens the possibility of new prophylactic strategies.

Animals↗
PubMed2002

[Physiopathology of meningoencephalitis caused by Cryptococcus neoformans].

Cryptococcus neoformans is an encapsulated yeast mainly responsible for meningoencephalitis, especially in AIDS patients. Recent observations using an experimental model of systemic cryptococcosis that mimics the human infection have reinforced the knowledge on the pathogenesis of cryptococcosis. Cryptococcosis may occur several years after inhalation of infecting particles from the environment. A stage of fungemia that reflects the dissemination of infection usually precedes the development of meningoencephalitis. The capsule mainly composed of glucuronoxylomannan constitutes the main virulence factor of C. neoformans. It has several deleterious effects including the inhibition of the host immune responses. The central nervous system involvement differs between AIDS patients and HIV-negative patients. In AIDS patients, histological studies of the brain show numerous cryptococci without significant inflammatory cell response. In other immunodepressed hosts, a granulomatous inflammation containing few yeasts is usually seen. This may reflect an altered local immunological defect against C. neoformans in AIDS patients with cryptococcosis.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Hybrid genotypes in the pathogenic yeast Cryptococcus neoformans.

Amplified fragment length polymorphism (AFLP) genotyping of isolates of the pathogenic fungus Cryptococcus neoformans suggested a considerable genetic divergence between the varieties C. neoformans var. neoformans and C. neoformans var. grubii on the one hand versus C. neoformans var. gattii on the other. This divergence is supported by additional phenotypic, biochemical, clinical and molecular differences. Therefore, the authors propose the existence of two species, C. neoformans (Sanfelice) Vuillemin and C. bacillisporus Kwon-Chung, which differ in geographical distribution, serotypes and ecological origin. Within each species three AFLP genotypes occur, which differ in geographical distribution and serotypes. Differences in ecological origin (AIDS patients, non-AIDS patients, animals or the environment) were found to be statistically not significant. In C. neoformans as well as in C. bacillisporus one of the genotypes represented a hybrid. The occurrence of hybridization has consequences for the reproductive biology of the species, as new genotypes with altered virulence or susceptibility to antifungal drugs may arise through the exchange of genetic material.

AIDS-Related Opportunistic Infections↗